10-substituted morphinan hydantoins

ABSTRACT

The application is directed to compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein R 1 -R 9 , Y, Z are defined as set forth in the specification. The invention is also directed to use of compounds of Formula (I) and the maceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.

BACKGROUND OF THE INVENTION

Field of the Invention

This application is in the field of medicinal chemistry. The applicationrelates to novel 10-substituted morphinan hydantoins and pharmaceuticalcompositions comprising one or more of these compounds. The applicationalso relates to the use of 10-substituted morphinan hydantoins.

Description of the Related Art

Pain is the most common symptom for which patients seek medical adviceand treatment. While acute pain is usually self-limited, chronic paincan persist for 3 months or longer and lead to significant changes in apatient's personality, lifestyle, functional ability and overall qualityof life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C.Bennett and F. Plum eds., 20th ed. 1996).

Pain has traditionally been managed by administering either a non-opioidanalgesic (such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflunisal ornaproxen), or an opioid analgesic (such as morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, oxymorphone, orbuprenorphine).

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes are known as μ, δ and κ. Asopiates have a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as endorphins, enkephalins, and dynorphins, respectively.Additional experimentation has led to the identification of the opioidreceptor-like (ORL-1) receptor, which has a high degree of homology tothe known opioid receptor classes. This more recently discoveredreceptor was classified as an opioid receptor based only on structuralgrounds, as the receptor did not exhibit pharmacological homology. Itwas initially demonstrated that non-selective ligands having a highaffinity for μ, δ and κ receptors had low affinity for the ORL-1receptor. This characteristic, along with the fact that an endogenousligand had not yet been discovered, led to the ORL-1 receptor beingdesignated as an “orphan receptor”.

Kappa (κ) opioid receptor agonists have been evaluated as alternativesto existing analgesics for the treatment of pain. Centrally penetratingκ agonists produce antinociceptive effects in conventional preclinicalassays of basal, inflammatory and neuropathic pain (Vanderah et al., J.Pharmacol. Exp. Ther. 310:326-333 (2004); Negus et al.,Psychopharmacology (Berl) 210:149-159 (2010)). However, centrallypenetrating κ agonists can also produce undesirable side-effects, suchas sedative and psychotomimetic effects (Pande et al., Clin.Neuropharmacol. 19:92-97 (1996); Pande et al., Clin. Neuropharmacol.19:451-456 (1996); and Wadenberg, CNS Drug Rev. 9:187-198 (2003)).

Opioid receptor agonists that do not readily cross the blood-brainbarrier are peripherically restricted and distribute poorly to thecentral nervous system after systemic administration. Such compoundswould retain an ability to produce analgesia by acting on peripheralopioid receptors, such as peripheral κ-opioid receptors, but theirpotency to produce centrally mediated side-effects would be reduced.

There is a need for effective analgesics that work by acting on opioidreceptors. There is also a need for analgesics that work by acting onperipheral opioid receptors. There is also a need for analgesics thatwork by acting on central opioid receptors. There is also a need foranalgesics that work by acting on κ-opioid receptors. There is also aneed for analgesics that work by acting on peripheral κ-opioidreceptors.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides compounds represented byFormulae I-XVII, below, and the pharmaceutically acceptable salts andsolvates thereof, collectively referred to herein as “Compounds of theInvention” (each is individually referred to hereinafter as a “Compoundof the Invention”).

In another aspect, the present disclosure provides the use of Compoundsof the Invention as synthesis intermediates.

In another aspect, the present disclosure provides the use of Compoundsof the Invention as modulators of one or more opioid receptors.Specifically, the present disclosure provides the use of Compounds ofthe Invention as modulators of μ, δ, κ, and/or ORL-1 opioid receptors,and especially modulators of μ and/or κ opioid receptors.

In another aspect, the present disclosure provides a method of treatingor preventing a disorder responsive to the modulation of one or moreopioid receptors in a patient, comprising administering to the patientan effective amount of a Compound of the Invention.

In another aspect, the present disclosure provides a use of a Compoundof the Invention as an analgesic to treat or prevent pain; or as anagent to treat or prevent withdrawal from alcohol or drug addiction; oras an agent to treat or prevent addictive disorders; or as an agent totreat a pruritic condition; or as an agent to treat or preventconstipation; or as an agent to treat or prevent diarrhea (each of pain,alcohol withdrawal, drug withdrawal, addictive disorders, pruritis,constipation, and diarrhea being a “Condition”).

The present invention further provides methods of treating or preventinga Condition, comprising administering to a patient in need thereof atherapeutically effective amount of a Compound of the Invention. Incertain embodiments, the Condition is pain (including acute pain,chronic pain (which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain), and surgical pain). TheCompounds of the Invention are particularly useful for treating orpreventing chronic pain.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a Compoundof the Invention and one or more pharmaceutically acceptable carriers.Such compositions are useful for treating or preventing a Condition in apatient.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of a disorder responsive tothe modulation of one or more opioid receptors. Preferably, the disorderis responsive to modulation of the μ-opioid receptor or the κ-opioidreceptor, or to modulation of both the μ-opioid receptor and theκ-opioid receptor.

In another aspect, the present disclosure provides a method ofmodulating one or more opioid receptors in a patient in need of saidmodulation, comprising administering to the patient an opioid receptormodulating amount of a Compound of the Invention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of one or more Conditionsin a patient in need of said treatment or prevention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of pain in a patient, suchas acute pain, chronic pain (which includes but is not limited to,neuropathic pain, postoperative pain, and inflammatory pain), orsurgical pain.

In another aspect, the present disclosure provides Compounds of theInvention for use in modulation of one or more opioid receptors in apatient.

In another aspect, the present disclosure provides use of Compounds ofthe Invention in the manufacture of a medicament for treating orpreventing a disorder responsive to the modulation of one or more opioidreceptors.

In another aspect, the present disclosure provides use of Compounds ofthe Invention in the manufacture of a medicament for modulating of oneor more opioid receptors in a patient. Preferably, the μ- or κ-opioidreceptor is modulated, or both the μ- and κ-opioid receptors aremodulated.

In another aspect, the present disclosure provides Compounds of theInvention for use as a medicament.

In another aspect, the present disclosure provides use of a Compound ofthe Invention in the manufacture of a medicament for treating orpreventing a Condition in a patient.

In another aspect, the present disclosure provides use of a Compound ofthe Invention in the manufacture of a medicament for treating orpreventing pain in a patient, such as acute pain, chronic pain, orsurgical pain.

In another aspect, the present disclosure provides a pharmaceuticalcomposition, comprising a Compound of the Invention for treating orpreventing a disorder responsive to the modulation of one or more opioidreceptors.

The present invention further provides methods for preparing apharmaceutical composition, comprising admixing a Compound of theInvention and a pharmaceutically acceptable carrier to form thepharmaceutical composition.

In another aspect, the present invention provides radiolabeled Compoundsof the Invention, especially ¹H, ¹¹C and ¹⁴C radiolabeled Compounds ofthe Invention, and the use of such compounds as radioligands to detectbinding to an opioid receptor in screening assays.

In another aspect, the present invention provides a method for screeninga candidate compound for the ability to bind to an opioid receptor,comprising a) introducing a fixed concentration of a radiolabeledCompound of the Invention to the receptor under conditions that permitbinding of the radiolabeled compound to the receptor to form a complex;b) titrating the complex with a candidate compound; and c) determiningthe binding of the candidate compound to said receptor.

In a further aspect, the invention relates to a kit, comprising asterile container containing an effective amount of a Compound of theInvention and instructions for therapeutic use.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Certain Compounds of the Invention are useful for modulating apharmacodynamic response from one or more opioid receptors (μ, δ, κ,ORL-1) either centrally or peripherally, or both. The pharmacodynamicresponse may be attributed to the compound either stimulating(agonizing) or inhibiting (antagonizing) the one or more receptors.Certain Compounds of the Invention may antagonize one or more opioidreceptors, while also agonizing one or more other receptors. Compoundsof the Invention having agonist activity may be either full or partialagonists.

One aspect of the invention is based on the use of certain Compounds ofthe Invention as synthesis intermediates.

In one embodiment, Compounds of the Invention are compounds representedby Formula I:

and the pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is hydrogen, hydroxy, halo, cyano, carboxy, or aminocarbonyl; oralkyl, alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy, any of whichis optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹⁰ groups; or —O-PG, wherein PG is a hydroxylprotecting group;

R² is

(a) hydrogen or carboxamido; or

(b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylalkyl, alkylcarbonyl,alkoxycarbonyl, (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹⁰ groups;

R³ is hydrogen, hydroxy, or halo; or alkoxy, alkylamino, ordialkylamino, any of which is optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹⁰ groups;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen; cycloalkyl; cycloalkenyl; heterocyclo; aryl; heteroaryl; alkyloptionally substituted with 1 or 2 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl,carboxamido, cycloalkyl, cycloalkenyl, heterocyclo, aryl, andheteroaryl; and an amine protecting group; wherein said cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups;

R⁶ is hydrogen and R⁷ is hydroxy, halogen, alkyl, or alkoxy; or

R⁶ and R⁷ together form ═O;

R⁸ and R⁹ are both hydrogen; or

R⁸ and R⁹ together with the carbon atoms to which they are attached forma linker —O— (that is, R⁸ and R⁹ together form a linker —O— between thecarbon atoms to which R⁸ and R⁹, respectively, are attached);

each R¹⁰ is independently selected from the group consisting of hydroxy,halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino,carboxy, alkoxy, and alkoxycarbonyl;

Y is C═O or CH₂;

Z is C═O or CHR¹¹;

wherein R¹¹ is hydrogen, C₁₋₆ alkyl, or phenyl optionally substitutedwith 1, 2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein R⁸ and R⁹ both are hydrogen, represented by FormulaII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷, Y, and Z are as defined in connection with Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula II, wherein Z is C═O, represented by Formula III:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷ and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷, and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula V:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷ and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VI:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷, and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁵, R⁷ and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VIII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁵ and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IX:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷ and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula X:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷ and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XI:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷ and Y are as defined for Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein R⁸ and R⁹ together with the carbon atoms to whichthey are attached form a linker —O—, represented by Formula XII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷, Y, and Z are as defined in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XIII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁷ and Y are as defined in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XIV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁵ and Y are as defined in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹-R⁵, R⁷, and Y are as defined in connection with Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I or Formula II, wherein Z is CHR¹¹, wherein R¹¹ is hydrogen,C₁₋₆ alkyl or phenyl optionally substituted with 1, 2, or 3independently selected R¹⁰ groups. In one embodiment, R¹¹ is C₁₋₆ alkyl,such as C₁₋₄ alkyl, and preferably methyl, ethyl, propyl, isopropyl, orsec-propyl. In another embodiment, R¹¹ is unsubstituted phenyl. Inanother embodiment, R¹¹ is phenyl substituted with 1, 2, or 3(preferably 1 or 2) independently selected R¹⁰ groups. Useful R¹⁰ groupsinclude hydroxy, halo, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, cyano, nitro, amino,C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, carboxy, C₁₋₆ alkoxy, and C₁₋₆alkoxycarbonyl, and preferably hydroxy, halo, C₁₋₄ alkyl,halo(C₁₋₄)alkyl, nitro, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino,carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl. In another embodiment,R¹¹ is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is hydrogen, hydroxy, halo, cyano,carboxy, or aminocarbonyl (i.e., —C(═O)NH₂). In another embodiment, R¹is hydroxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, or alkynyloxy, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl, wherein said aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, or C₂₋₆ alkynyloxy, any of whichis optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,halo(C₁₋₆)alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, carboxy,C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 5- or 6-membered heterocyclo, C₃₋₇ cycloalkyl, and C₃₋₇cycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹⁰ groups. Useful R¹⁰ groups include hydroxy,halo, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, cyano, nitro, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, carboxy, C₁₋₆ alkoxy, and C₁₋₆ alkoxycarbonyl, andpreferably hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl. In another embodiment, R¹ is C₁₋₆ alkoxy, C₂₋₆alkenyloxy, or C₂₋₆ alkynyloxy, any of which are optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is unsubstituted C₁₋₆ alkoxy,unsubstituted C₂₋₆ alkenyloxy, or unsubstituted C₂₋₆ alkynyloxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is unsubstituted methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, iso-butoxy, orsec-butoxy, and advantageously R¹ is unsubstituted methoxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is unsubstituted ethenoxy, propenoxy,isopropenoxy, butenoxy, or sec-butenoxy. In another embodiment, R¹ isunsubstituted ethynoxy, propynoxy, butynoxy, or 2-butynoxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is unsubstituted C₁₋₆ alkoxy orhydroxy, and preferably unsubstituted C₁₋₄ alkoxy (such as, for example,methoxy) or hydroxy. In another embodiment, R¹ is unsubstituted C₁₋₄alkoxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is hydrogen or carboxamido. In thisaspect of the invention, preferably R² is hydrogen, —CONH₂, —CON(H)C₁₋₄alkyl, —CON(C₁₋₄ alkyl)₂, or —CON(H)Ph. In one embodiment, R² ishydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, 5- or 6-memberedheterocyclo, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₃₋₇cycloalkyl(C₁₋₄)alkyl, C₃₋₇ cycloalkenyl(C₁₋₄)alkyl, 5- or 6-memberedheterocyclo(C₁₋₄)alkyl, C₆₋₁₀ aryl(C₁₋₄)alkyl, 5- or 6-memberedheteroaryl(C₁₋₄)alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₆₋₁₀aryl(C₁₋₄)alkoxycarbonyl, or 5- or 6-memberedheteroaryl(C₁₋₄)alkoxycarbonyl, any of which is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, C₁₋₆ alkyl, halo, halo(C₁₋₆)alkyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, carboxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, 5- or6-membered heterocyclo, C₃₋₇ cycloalkyl, and C₃₋₇ cycloalkenyl, whereinsaid aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups. Useful R¹⁰ groups are those described above in connection withR.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, 5- or 6-memberedheterocyclo, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₃₋₇(cycloalkyl)(C₁₋₄)alkyl, C₃₋₇ (cycloalkenyl)(C₁₋₄)alkyl, 5- or6-membered heterocyclo(C₁₋₄)alkyl, C₆₋₁₀ aryl(C₁₋₄)alkyl, 5- or6-membered heteroaryl(C₁₋₄)alkyl, C₁₋₄ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₆₋₁₀ aryl(C₁₋₄)alkoxycarbonyl, or 5- or 6-memberedheteroaryl(C₁₋₄)alkoxycarbonyl, any of which is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄alkoxycarbonyl, and preferably optionally substituted with 1 or 2substituents, each independently selected from the group consisting ofhydroxy, methyl, ethyl, halo, trifluoromethyl, amino, methylamino,ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy,methoxycarbonyl, and ethoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is unsubstituted C₁₋₆ alkyl, andpreferably unsubstituted C₁₋₄ alkyl, such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, or tert-butyl, and more preferably methyl or ethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is C₃₋₇ (cycloalkyl)(C₁₋₄)alkyl or C₃₋₇(cycloalkenyl)(C₁₋₄)alkyl, and especially C₃₋₇ (cycloalkyl)(C₁₋₄)alkyl,such as cyclopropyl(C₁₋₄)alkyl, cyclobutyl(C₁₋₄)alkyl,cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl, optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄alkoxycarbonyl, and preferably optionally substituted with 1 or 2substituents, each independently selected from the group consisting ofhydroxy, methyl, ethyl, halo, trifluoromethyl, amino, methylamino,ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy,methoxycarbonyl, and ethoxycarbonyl. In another embodiment, R² isunsubstituted cyclopropyl(C₁₋₄)alkyl. In another embodiment, R² isunsubstituted cyclohexyl(C₁₋₄)alkyl, such as cyclohexylmethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is unsubstituted (cyclopropyl)methyl,2-(cyclopropyl)ethyl or 3-(cyclopropyl)propyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is C₁₋₆ alkyl, and preferably C₁₋₄alkyl, substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of halo (such as fluoro),halo(C₁₋₄)alkyl (such as, for example, trifluoro(C₁₋₂)alkyl), phenyl,and heterocyclo (such as tetrahydropyranyl). In one embodiment of thisaspect of the invention, R² is benzyl, phenethyl, 3-phenylpropyl,tetrahydropyran-4-ylmethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or 2,2-difluoroethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R² is C₂₋₆ alkenyl, and preferably C₂₋₄alkenyl, which is unsubstituted or substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofC₁₋₄ alkyl (such as methyl), halo (such as fluoro), halo(C₁₋₄)alkyl(such as, for example, trifluoro(C₁₋₂)alkyl), phenyl, and heterocyclo(such as tetrahydropyranyl). In one embodiment of this aspect of theinvention, R² is 3-methyl-but-2-enyl, 3-methylbut-3-enyl, or4-phenylbut-2-enyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R³ is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R³ is hydroxy or halo. In anotherembodiment, R³ is hydroxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R³ is alkoxy, alkylamino, or dialkylamino,any of which is optionally substituted with 1, 2, or 3 substituents,each independently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R³ is C₁₋₆ alkoxy, C₁₋₆ alkylamino, ordi(C₁₋₆)alkylamino, any of which is optionally substituted with 1, 2, or3 substituents, each independently selected from the group consisting ofhydroxy, halo, halo(C₁₋₆)alkyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, carboxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₆₋₁₀aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclo, C₃₋₇cycloalkyl, and C₃₋₇ cycloalkenyl, wherein said aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R¹⁰ groups. Useful R¹⁰ groups arethose described above in connection with R¹.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R³ is unsubstituted C₁₋₆ alkoxy or C₁₋₆alkoxy substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, halo(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ and R⁵ are each independently selectedfrom the group consisting of hydrogen; cycloalkyl; cycloalkenyl;heterocyclo; aryl; heteroaryl; and alkyl optionally substituted with 1or 2 substituents, each independently selected from the group consistingof hydroxy, halo, haloalkyl, cyano, nitro, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl, wherein saidcycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ and R⁵ are each independently selectedfrom the group consisting of hydrogen; C₃₋₆ cycloalkyl; C₃₋₆cycloalkenyl; 5- or 6-membered heterocyclo; phenyl; 5- or 6-memberedheteroaryl; and C₁₋₆ alkyl (preferably C₁₋₄ alkyl) optionallysubstituted with 1 or 2 substituents, each independently selected fromthe group consisting of hydroxy, halo, haloalkyl, cyano, nitro, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, carboxamido,cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl; whereinsaid cycloalkyl, cycloalkenyl, heterocyclo, phenyl, aryl, and heteroarylare optionally substituted with 1, 2, or 3 independently selected R¹⁰groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ and R⁵ are each independently hydrogenor alkyl optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl, wherein said cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ and R⁵ are each independently selectedfrom the group consisting of hydrogen and C₁₋₆ alkyl, and preferablyC₁₋₄ alkyl, optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl, wherein said cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups. Inanother embodiment, R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen and C₁₋₆ alkyl, and preferably C₁₋₄ alkyl,optionally substituted with 1 or 2 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, andalkoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein either R⁴ or R⁵ is an amine protectinggroup and the other one is selected from the group consisting ofhydrogen; cycloalkyl; cycloalkenyl; heterocyclo; aryl; heteroaryl; andalkyl optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl; wherein said cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups. In oneembodiment, the amine protecting group is —CH₂—O—(CH₂)₂—Si(CH₃)₃.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ and R⁵ are both hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ is hydrogen and R⁵ is C₁₋₆ alkyloptionally substituted with 1 or 2 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl,carboxamido, cycloalkyl, cycloalkenyl, heterocyclo, aryl, andheteroaryl, wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl,and heteroaryl are optionally substituted with 1, 2, or 3 independentlyselected R¹⁰ groups, and preferably optionally substituted with 1 or 2substituents, each independently selected from the group consisting ofhydroxy, halo, halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl,carboxamido, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 5- or 6-memberedheterocyclo, phenyl, and 5- or 6-membered heteroaryl, wherein saidcycloalkyl, cycloalkenyl, heterocyclo, phenyl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ is hydrogen and R⁵ is unsubstitutedC₁₋₆ alkyl, and more preferably unsubstituted C₁₋₄ alkyl, such as methylor ethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ is hydrogen and R⁵ is C₁₋₄ alkyl (suchas methyl) substituted with halo(C₁₋₄)alkyl (such as trifluoromethyl),cyano, C₃₋₆ cycloalkyl (such as cyclopropyl), or phenyl, wherein saidphenyl is optionally substituted with 1 or 2 groups, each independentlyselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl,halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁-4 alkoxy, and C₁₋₄ alkoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ is hydrogen and R⁵ is benzyl, whereinthe phenyl group is unsubstituted or substituted with 1 or 2 groups eachindependently selected from the group consisting of hydroxy, halo,trifluoromethyl, methoxy, carboxy, cyano and nitro.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ is hydrogen and R⁵ is cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl, wherein saidcycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups. In another embodiment, R⁵ is selected from the group consistingof C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 5- or 6-membered heterocyclo,phenyl, and 5- or 6-membered heteroaryl, wherein said cycloalkyl,cycloalkenyl, heterocyclo, phenyl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups. Inanother embodiment, R⁴ is hydrogen and R⁵ is unsubstituted phenyl orphenyl substituted with 1, 2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁵ is hydrogen and R⁴ is C₁₋₆ alkyloptionally substituted with 1 or 2 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl,carboxamido, cycloalkyl, cycloalkenyl, heterocyclo, aryl, andheteroaryl, wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl,and heteroaryl are optionally substituted with 1, 2, or 3 independentlyselected R¹⁰ groups, and preferably optionally substituted with 1 or 2substituents, each independently selected from the group consisting ofhydroxy, halo, halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, 5- or 6-membered heterocyclo, phenyl, and5- or 6-membered heteroaryl, wherein cycloalkyl, cycloalkenyl,heterocyclo, phenyl, and heteroaryl are optionally substituted with 1,2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁵ is hydrogen and R⁴ is unsubstitutedC₁₋₆ alkyl, and more preferably R⁴ is unsubstituted C₁₋₄ alkyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁵ is hydrogen and R⁴ is C₁₋₄ alkyl (suchas methyl) substituted with halo(C₁₋₄ alkyl) (such as trifluoromethyl),cyano, C₃₋₆ cycloalkyl (such as cyclopropyl), or phenyl, wherein saidphenyl is optionally substituted with 1 or 2 groups, each independentlyselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl,halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁵ is hydrogen and R⁴ is benzyl, whereinthe phenyl group is unsubstituted or substituted with 1 or 2 groups eachindependently selected from the group consisting of hydroxy, halo,trifluoromethyl, methoxy, carboxy, cyano and nitro.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁵ is hydrogen and R⁴ is cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl, wherein saidcycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups. In another embodiment, R⁴ is selected from the group consistingof C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 5- or 6-membered heterocyclo,phenyl, and 5- or 6-membered heteroaryl, wherein said cycloalkyl,cycloalkenyl, heterocyclo, phenyl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups. Inanother embodiment, R⁵ is hydrogen and R⁴ is unsubstituted phenyl orphenyl substituted with 1, 2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R⁴ and R⁵ are each independently C₁₋₆alkyl optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl, wherein said cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups; andpreferably optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of hydroxy, halo,halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl,carboxamido, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 5- or 6-memberedheterocyclo, phenyl, and 5- or 6-membered heteroaryl, whereincycloalkyl, cycloalkenyl, heterocyclo, phenyl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein both R⁴ and R⁵ are independentlyunsubstituted C₁₋₆ alkyl, and more preferably independentlyunsubstituted C₁₋₄ alkyl. In another embodiment, both R⁴ and R⁵ aremethyl or ethyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein both R⁴ and R⁵ are independently C₁₋₆alkyl, and more preferably C₁₋₄ alkyl, substituted with 1 or 2substituents, each independently selected from the group consisting ofhydroxy, halo, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl, wherein said cycloalkyl,cycloalkenyl, heterocyclo, aryl, and heteroaryl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups. Inanother embodiment, both R⁴ and R⁵ are independently C₁₋₄ alkylsubstituted with 1 or 2 substituents, each independently selected fromthe group consisting of hydroxy, halo, halo(C₁₋₄)alkyl, cyano, nitro,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, C₁₋₄alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 5- or 6-memberedheterocyclo, phenyl, and 5- or 6-membered heteroaryl, wherein saidcycloalkyl, cycloalkenyl, heterocyclo, phenyl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups. In another embodiment, both R⁴ and R⁵ are methyl eachindependently substituted with trifluoromethyl, cyano, cyclopropyl,unsubstituted phenyl, or phenyl substituted with hydroxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein both R⁴ and R⁵ are independentlycycloalkyl, cycloalkenyl, heterocyclo, aryl, or heteroaryl, wherein saidcycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups. In another embodiment, R⁴ and R⁵ are each independently selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 5- or6-membered heterocyclo, phenyl, and 5- or 6-membered heteroaryl, whereinsaid cycloalkyl, cycloalkenyl, heterocyclo, phenyl, and heteroaryl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups. In another embodiment, R⁴ and R⁵ are both unsubstituted phenylor phenyl substituted with 1, 2, or 3 independently selected R¹⁰ groups.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is C═O.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is CH₂.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is C═O and R⁴ and R⁵ are both hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is C═O, R⁴ is hydrogen or C₁₋₄ alkyl andR⁵ is phenyl, optionally substituted with 1, 2, or 3 independentlyselected R¹⁰ groups, or C₁₋₄ alkyl (such as methyl) optionallysubstituted with halo(C₁₋₄ alkyl) (such as trifluoromethyl), cyano, C₃₋₆cycloalkyl (such as cyclopropyl), or phenyl, wherein said phenyl isoptionally substituted with 1, 2, or 3 independently selected R¹⁰ groups(e.g., 1, 2, or 3 groups each independently selected from the groupconsisting of hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl).

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is C═O, R⁵ is hydrogen or C₁₋₄ alkyl andR⁴ is phenyl, optionally substituted with 1, 2, or 3 independentlyselected R¹⁰ groups, or C₁₋₄ alkyl (such as methyl) optionallysubstituted with halo(C₁₋₄ alkyl) (such as trifluoromethyl), cyano, C₃₋₆cycloalkyl (such as cyclopropyl), or phenyl, wherein said phenyl isoptionally substituted with 1, 2, or 3 independently selected R¹⁰ groups(e.g., 1, 2, or 3 groups each independently selected from the groupconsisting of hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl).

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is CH₂ and R⁴ and R⁵ are both hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is CH₂, R⁴ is hydrogen or C₁₋₄ alkyl andR⁵ is phenyl, optionally substituted with 1, 2, or 3 independentlyselected R¹⁰ groups, or C₁₋₄ alkyl (such as methyl) optionallysubstituted with halo(C₁₋₄ alkyl) (such as trifluoromethyl), cyano, C₃₋₆cycloalkyl (such as cyclopropyl), or phenyl, wherein said phenyl isoptionally substituted with 1, 2, or 3 independently selected R¹⁰ groups(e.g., 1, 2, or 3 groups each independently selected from the groupconsisting of hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl).

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is CH₂, R⁵ is hydrogen or C₁₋₄ alkyl andR⁴ is phenyl, optionally substituted with 1, 2, or 3 independentlyselected R¹⁰ groups, or C₁₋₄ alkyl (such as methyl) optionallysubstituted with halo(C₁₋₄ alkyl) (such as trifluoromethyl), cyano, C₃₋₆cycloalkyl (such as cyclopropyl), or phenyl, wherein said phenyl isoptionally substituted with 1, 2, or 3 independently selected R¹⁰ groups(e.g., 1, 2, or 3 groups each independently selected from the groupconsisting of hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl).

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is C═O, R¹ is hydroxy or unsubstitutedC₁₋₆ alkoxy; R² is unsubstituted C₁₋₄ alkyl, or cyclopropyl(C₁₋₄)alkyl,cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl,optionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, C₁₋₄ alkyl, halo,halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl; R³ ishydrogen or hydroxy; and R⁴ and R⁵ are each independently selected fromthe group consisting of hydrogen; phenyl optionally substituted with 1,2, or 3 independently selected R¹⁰ groups; and C₁₋₄ alkyl (such asmethyl) optionally substituted with halo(C₁₋₄ alkyl) (such astrifluoromethyl), cyano, C₃₋₆ cycloalkyl (such as cyclopropyl), orphenyl, wherein said phenyl is optionally substituted with 1, 2, or 3independently selected R¹⁰ groups (e.g., 1, 2, or 3 groups eachindependently selected from the group consisting of hydroxy, halo, C₁₋₄alkyl, halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl). Inanother embodiment, R⁴ and R⁵ are both hydrogen. In another embodiment,R² is unsubstituted cyclopropyl(C₁₋₄)alkyl. In another embodiment, R² isunsubstituted C₁₋₆ alkyl, such as methyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is C═O, R¹ is hydroxy or unsubstitutedC₁₋₆ alkoxy; R² is unsubstituted C₁₋₄ alkyl, or cyclopropyl(C₁₋₄)alkyl,cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl,optionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, C₁₋₄ alkyl, halo,halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl; R³ ishydrogen or hydroxy; and R⁴ and R⁵ are both hydrogen. In anotherembodiment, R² is unsubstituted cyclopropyl(C₁₋₄)alkyl. In anotherembodiment, R² is unsubstituted C₁₋₆ alkyl, such as methyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is CH₂, R¹ is hydroxy or unsubstitutedC₁₋₆ alkoxy; R² is unsubstituted C₁₋₄ alkyl, or cyclopropyl(C₁₋₄)alkyl,cyclobutyl(C₁ 0.4)alkyl, cyclopentyl(C₁₋₄)alkyl, orcyclohexyl(C₁₋₄)alkyl, optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄alkoxycarbonyl; R³ is hydrogen or hydroxy; and R⁴ and R⁵ are eachindependently selected from the group consisting of hydrogen; phenyl,optionally substituted with 1, 2, or 3 independently selected R¹⁰groups; and C₁₋₄ alkyl (such as methyl) optionally substituted withhalo(C₁₋₄ alkyl) (such as trifluoromethyl), cyano, C₃₋₆ cycloalkyl (suchas cyclopropyl), or phenyl, wherein said phenyl is optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups (e.g., 1,2, or 3 groups each independently selected from the group consisting ofhydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄alkoxycarbonyl). In another embodiment, R² is unsubstitutedcyclopropyl(C₁₋₄)alkyl. In another embodiment, R² is unsubstituted C₁₋₆alkyl, such as methyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is CH₂, R¹ is hydroxy or unsubstitutedC₁₋₆ alkoxy; R² is unsubstituted C₁₋₄ alkyl, or cyclopropyl(C₁₋₄)alkyl,cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl,optionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, C₁₋₄ alkyl, halo,halo(C₁₋₄)alkyl, cyano, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl; R³ ishydrogen or hydroxy; and R⁴ and R⁵ are both hydrogen. In anotherembodiment, R² is unsubstituted cyclopropyl(C₁₋₄)alkyl. In anotherembodiment, R² is unsubstituted C₁₋₆ alkyl, such as methyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is C═O, R¹ is hydroxy or unsubstitutedC₁₋₆ alkoxy; R² is C₁₋₆ alkyl (preferably C₁₋₄ alkyl) substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of halo (such as fluoro), halo(C₁₋₄)alkyl (such as, forexample, trifluoro(C₁₋₂)alkyl), phenyl, and heterocyclo (such astetrahydropyranyl); unsubstituted C₂₋₆ alkenyl (preferably C₂₋₄alkenyl); or C₂₋₆ alkenyl (preferably C₂₋₄ alkenyl) substituted with 1,2, or 3 substituents, each independently selected from the groupconsisting of C₁₋₄ alkyl (such as methyl), halo (such as fluoro),halo(C₁₋₄)alkyl (such as, for example, trifluoro(C₁₋₂)alkyl), phenyl,and heterocyclo (such as tetrahydropyranyl); R³ is hydrogen or hydroxy;and R⁴ and R⁵ are each independently selected from the group consistingof hydrogen; phenyl, optionally substituted with 1, 2, or 3independently selected R¹⁰ groups; and C₁₋₄ alkyl (such as methyl)optionally substituted with halo(C₁₋₄ alkyl) (such as trifluoromethyl),cyano, C₃₋₆ cycloalkyl (such as cyclopropyl), or phenyl, wherein saidphenyl is optionally substituted with 1, 2, or 3 independently selectedR¹⁰ groups (e.g., 1, 2, or 3 groups each independently selected from thegroup consisting of hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano,nitro, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy,and C₁₋₄ alkoxycarbonyl). In another embodiment, R⁴ and R⁵ are bothhydrogen.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein Y is CH₂, R¹ is hydroxy or unsubstitutedC₁₋₆ alkoxy; R² is C₁₋₆ alkyl (preferably C₁₋₄ alkyl) substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of halo (such as fluoro), halo(C₁₋₄)alkyl (such as, forexample, trifluoro(C₁₋₂)alkyl), phenyl, and heterocyclo (such astetrahydropyranyl); unsubstituted C₂₋₆ alkenyl (preferably C₂₋₄alkenyl); or C₂₋₆ alkenyl (preferably C₂₋₄ alkenyl) substituted with 1,2, or 3 substituents, each independently selected from the groupconsisting of C₁₋₄ alkyl (such as methyl), halo (such as fluoro),halo(C₁₋₄)alkyl (such as, for example, trifluoro(C₁₋₂)alkyl), phenyl,and heterocyclo (such as tetrahydropyranyl); R³ is hydrogen or hydroxy;and R⁴ and R⁵ are each independently selected from the group consistingof hydrogen; phenyl, optionally substituted with 1, 2, or 3independently selected R¹⁰ groups; and C₁₋₄ alkyl (such as methyl)optionally substituted with halo(C₁₋₄ alkyl) (such as trifluoromethyl),cyano, C₃₋₆ cycloalkyl (such as cyclopropyl), or phenyl, wherein saidphenyl is optionally substituted with 1, 2, or 3 independently selectedR¹⁰ groups (e.g., 1, 2, or 3 groups each independently selected from thegroup consisting of hydroxy, halo, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, cyano,nitro, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy,and C₁₋₄ alkoxycarbonyl). In another embodiment, R⁴ and R⁵ are bothhydrogen.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein R² is (cyclopropyl)methyl, and R⁴, R⁵, R⁸, and R⁹ areeach hydrogen, represented by Formula XVI:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹² is H or C₁₋₆ alkyl optionally substituted with 1 or 2 substituents,each independently selected from the group consisting of hydroxy, halo,halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy,C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl, and R³, R⁶, R⁷, and Y are asdefined for Formula I. In one embodiment, Y is C(═O) and R³ is hydrogen,hydroxy, unsubstituted C₁₋₆ alkoxy, or C₁₋₆ alkoxy substituted with 1,2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl. Inanother embodiment, Y is C(═O) and R³ is hydrogen or hydroxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-VII, IX-XIII, XV, and XVI, wherein R⁶ is hydrogen andR⁷ is hydroxy, halogen, alkyl, or alkoxy; preferably, R⁷ is hydroxy,halogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and more preferably R⁷ is hydroxy,halogen (such as fluoro), C₁₋₄ alkyl, or C₁₋₄ alkoxy.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XIV and XVI, wherein R⁶ and R⁷ together form ═O.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-VI and IX-XIII, and XVI, wherein R⁶ is hydrogen and R⁷is hydroxy or halogen, or R⁶ and R⁷ together form ═O.

In another embodiment, Compounds of the Invention include:

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Invention include:

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XV, wherein R¹ is —O-PG, wherein PG is a hydroxylprotecting group.

In another embodiment, Compounds of the Invention are compounds ofFormula I, represented by Formula XVII:

wherein R²-R⁹, Y, and PG are as defined for Formula I. Suitable andpreferable definitions for R²-R⁹ are those described above for any ofFormulae I-XV.

Suitable hydroxyl protecting groups for PG are well known and include,for example, any suitable hydroxyl protecting group disclosed in Wuts,P. G. M. & Greene, T. W., Greene's Protective Groups in OrganicSynthesis, 4rd Ed., pp. 16-430 (J. Wiley & Sons, 2007), hereinincorporated by reference in its entirety. The term “hydroxyl protectinggroup” as used herein refers to a group that blocks (i.e., protects) thehydroxy functionality while reactions are carried out on otherfunctional groups or parts of the molecule. Those skilled in the artwill be familiar with the selection, attachment, and cleavage ofprotecting groups and will appreciate that many different protectivegroups are known in the art, the suitability of one protective group oranother being dependent on the particular synthetic scheme planned.Suitable hydroxy protecting groups are generally able to be selectivelyintroduced and removed using mild reaction conditions that do notinterfere with other portions of the subject compounds. These protectinggroups can be introduced or removed at a convenient stage using methodsknown in the art. The chemical properties of such groups, methods fortheir introduction and removal are known in the art and can be found,for example, in Greene, T. W. and Wuts, P. G. M., above. Additionalhydroxyl protecting groups can be found, for example, in U.S. Pat. No.5,952,495, U.S. Patent Appl. Pub. No. 2008/0312411, WO 2006/035195, andWO 98/02033, which are herein incorporated by reference in theirentireties. Suitable hydroxyl protecting groups include themethoxymethyl, tetrahydropyranyl, tert-butyl, allyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl,benzoyl, benzyl (Bn), and p-methoxybenzyl group.

It will be apparent to a person of ordinary skill in the art in view ofthis disclosure that certain groups included in the definitions of —O-PGoverlap with the other definitions for R¹, such as methoxy, tert-butoxy,etc., and, thus, certain Compounds of the Invention having R¹ groupsthat include groups acting as hydroxyl protecting groups can bepharmaceutically active as described herein.

In one embodiment, the hydroxyl protecting group PG is selected from thegroup consisting of alkyl, arylalkyl, heterocyclo, (heterocyclo)alkyl,acyl, silyl, and carbonate, any of which are optionally substituted.

In another embodiment, the hydroxyl protecting group PG is an alkylgroup, typically an optionally substituted C₁₋₆ alkyl group, andsuitably unsubstituted methyl or tert-butyl.

In another embodiment, the hydroxyl protecting group PG is an arylalkylgroup. Suitable arylalkyl groups include, for example, an unsubstitutedbenzyl group, substituted benzyl groups, such as p-methoxybenzyl, andnaphthylmethyl.

In another embodiment, the hydroxyl protecting group PG is a heterocyclogroup, such as unsubstituted tetrahydropyranyl or optionally substitutedtetrahydropyranyl.

In another embodiment, the hydroxyl protecting group PG is a(heterocyclo)alkyl group. Suitable (heterocyclo)alkyl groups include,for example, 4-morpholinyl(C₁₋₄)alkyl groups, such as,2-(4-morpholinyl)ethyl.

In another embodiment, the hydroxyl protecting group PG is a silylgroup. The term “silyl” as employed herein refers to the group havingthe following structure:

wherein R¹³, R¹⁴, and R¹⁵ are each independently selected from the groupconsisting of alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl,any of which is optionally substituted. In one embodiment, the silylgroup is trimethyl silyl, tert-butyldimethyl silyl, tert-butyldiphenylsilyl, or tri-isopropyl silyl.

In another embodiment, the hydroxyl protecting group PG is an acylgroup. The term “acyl” as employed herein refers to the followingstructure:

wherein R¹⁶ is alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl,any of which is optionally substituted. The acyl group can be, forexample, C₁₋₄ alkylcarbonyl (such as, for example, acetyl), arylcarbonyl(such as, for example, benzoyl), levulinoyl, or pivaloyl. In anotherembodiment, the acyl group is benzoyl.

In another embodiment, the hydroxyl protecting group is a carbonategroup. The term “carbonate” as employed herein refers to the followingstructure:

wherein R¹⁷ is alkyl, alkenyl, cycloalkyl, aryl, (cycloalkyl)alkyl, orarylalkyl, any of which is optionally substituted. Typically, R¹⁷ isC₁₋₁₀ alkyl (e.g., 2,4-dimethylpent-3-yl), C₂₋₆ alkenyl (e.g., ethenylor prop-2-enyl, i.e., allyl), C₃₋₁₂ cycloalkyl (e.g., adamantyl),phenyl, or benzyl. In one embodiment, the carbonate is(benzyloxy)carbonyl.

The term “amine protecting group” as used herein refers to a group thatblocks (i.e., protects) the amine functionality while reactions arecarried out on other functional groups or parts of the molecule. Thoseskilled in the art will be familiar with the selection, attachment, andcleavage of amine protecting groups and will appreciate that manydifferent protective groups are know in the art, the suitability of oneprotective group or another being dependent on the particular syntheticscheme planned. Treatises on the subject are available for consultation,such as Wuts, P. G. M. & Greene, T. W., Greene's Protective Groups inOrganic Synthesis, 4rd Ed. (J. Wiley & Sons, 2007), herein incorporatedby reference in its entirety. Suitable amine protecting groups include—CH₂—O—(CH₂)₂—Si(CH₃)₃, carbobenzyloxy (Cbz), tert-butyloxycarbonyl(BOC), 9-fluorenylmethyloxycarbonyl (FMOC), and benzyl (Bn) groups. Itwill be apparent to a person of ordinary skill in the art in view ofthis disclosure that certain groups included in the definition “amineprotecting group” overlap with the other definitions for R⁴ and R⁵, suchas benzyl, and, thus, certain Compounds of the Invention having R⁴ or R⁵groups that include groups acting as amine protecting groups can bepharmaceutically active as described herein.

Optional substituents attached to aryl, phenyl and heteroaryl rings eachtake the place of a hydrogen atom that would otherwise be present in anyposition on the aryl, phenyl or heteroaryl rings.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chain and branched-chainC₁₋₁₀ alkyl groups. Typical C₁₋₁₀ alkyl groups include methyl (Me),ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,and n-decyl, isopropyl, sec-butyl, tert-butyl, iso-butyl, iso-pentyl,neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,1,3-dimethylheptyl, and 3,3-dimethylheptyl, among others. In oneembodiment, useful alkyl groups are selected from straight-chain andbranched-chain C₁₋₆ alkyl groups, i.e., straight chain C₁₋₆ alkyl groupsand branched chain C₃₋₆ alkyl groups. Typical C₁₋₆ alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, pentyl, 3-pentyl, hexyl, among others. In one embodiment,useful alkyl groups are selected from straight chain C₂₋₆ alkyl groupsand branched chain C₃₋₆ alkyl groups. Typical C₂₋₆ alkyl groups includeethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl,pentyl, 3-pentyl, hexyl among others. In one embodiment, useful alkylgroups are selected from straight-chain and branched-chain C₁₋₄ alkylgroups, i.e., straight chain C₁₋₄ alkyl groups and branched chain C₃₋₄alkyl groups. Typical C₁₋₄ alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl. In thisapplication, a C₁₋₆ alkyl group refers to straight-chain andbranched-chain C₁₋₆ alkyl groups, and a C₁₋₄ alkyl group refers tostraight-chain and branched-chain C₁₋₄ alkyl groups, as defined above inthis paragraph.

Useful alkenyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl. TypicalC₂₋₆ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,sec-butenyl, pentenyl, and hexenyl. Typical C₂₋₄ alkenyl groups includeethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

Useful alkynyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl. TypicalC₂₋₆ alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,pentynyl, and hexynyl groups. Typical C₂₋₄ alkynyl groups includeethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, preferably any of the above-mentioned C₁₋₆ alkyl groups, andpreferably any of the above-mentioned C₁₋₄ alkyl groups, substituted byone or more fluorine, chlorine, bromine or iodine atoms (e.g.,fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethylgroups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, preferably any of the above-mentioned C₁₋₆ alkyl groups,and preferably any of the above-mentioned C₁₋₄ alkyl groups, substitutedby one or more hydroxy groups, such as monohydroxyalkyl anddihydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, hydroxypentyl, and hydroxyhexyl groups, and especiallyhydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,2-hydroxypropyl, 2-hydroxyprop-2-yl, 3-hydroxypropyl,2,3-dihydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl,2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl). In oneembodiment, the monohydroxyalkyl is monohydroxy(C₁₋₄)alkyl. In oneembodiment, the dihydroxyalkyl is dihydroxy(C₁₋₄)alkyl.

Useful cycloalkyl groups are selected from saturated cyclic hydrocarbongroups containing 1, 2, or 3 rings having 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 carbon atoms (i.e., C₃-C₁₂ cycloalkyl) or the number of carbonsdesignated. In one embodiment, the cycloalkyl has one or two rings. Inanother embodiment, the cycloalkyl is a C₃-C₈ cycloalkyl. In anotherembodiment, the cycloalkyl is C₃₋₇ cycloalkyl. In another embodiment,the cycloalkyl is C₃₋₆ cycloalkyl. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornyl, decalin, and adamantyl.

Useful cycloalkenyl groups are selected from partially unsaturated(i.e., containing one or two double bonds) cyclic hydrocarbon groupscontaining 1, 2, or 3 rings having 4, 5, 6, 7, 8, 9, 10, 11, or 12carbon atoms (i.e., C₄-C₁₂ cycloalkenyl) or the number of carbonsdesignated. In one embodiment, the cycloalkenyl has one or two rings. Inanother embodiment, the cycloalkenyl is a C₃-C₈ cycloalkenyl. In anotherembodiment, the cycloalkenyl is C₃₋₇ cycloalkenyl. In anotherembodiment, the cycloalkenyl is C₃₋₆ cycloalkenyl. In one embodiment,the cycloalkenyl group contains one double bond. Exemplary cycloalkenylgroups containing one double bond include cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, andcyclodecenyl. In another embodiment, the cycloalkenyl group contains twodouble bonds. Preferably, the cycloalkenyl groups containing two doublebonds have 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C₅-C₁₂cycloalkadienyl). Exemplary cycloalkenyl groups having two double bondsinclude cyclopentadienyl, cyclohexadienyl, cycloheptadienyl,cyclooctadienyl, cyclononadienyl, and cyclodecadienyl.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy,iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, pentyloxy,hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy), preferably by oneof the C₁₋₆ alkyl groups, and more preferably by one of the C₁₋₄ alkylgroups.

Useful alkenyloxy groups include oxygen substituted by one of the C₂₋₆alkenyl groups, and preferably by one of the C₂₋₄ alkenyl groups,mentioned above (e.g., ethenyloxy, propenyloxy, isopropenyloxy,butenyloxy, sec-butenyloxy, pentenyloxy, and hexenyloxy).

Useful alkynyloxy groups include oxygen substituted by one of the C₂₋₆alkynyl groups, preferably by one of the C₂₋₄ alkynyl groups, mentionedabove (e.g., ethynyloxy, propynyloxy, butynyloxy, 2-butynyloxy,pentynyloxy, and hexynyloxy).

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted with any of the above-mentioned alkoxy groups (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, propoxymethyl,iso-propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups, and preferably one of the C₁₋₆ haloalkyl groups,mentioned above (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy,and 2,2,2-trifluoroethoxy).

Useful (cycloalkyl)alkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted with any of the above-mentioned cycloalkyl groups(e.g., (cyclopropyl)methyl, 2-(cyclopropyl)ethyl, (cyclopropyl)propyl,(cyclobutyl)methyl, (cyclopentyl)methyl, and (cyclohexyl)methyl).

Useful (cycloalkenyl)alkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted with any of the above-mentioned cycloalkenyl groups(e.g., (cyclobutenyl)methyl, 2-(cyclobutenyl)ethyl,(cyclobutenyl)propyl, (cyclopentenyl)methyl, (cyclohexenyl)methyl, and(cyclopentadienyl)methyl).

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl (Ph), naphthyl, phenanthryl, anthracyl,indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, morepreferably phenyl, naphthyl, and biphenyl groups.

Useful aryloxy groups include oxygen substituted by one of the arylgroups mentioned above (e.g., phenoxy).

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted by any of the above-mentioned aryl groups (e.g., benzyl andphenethyl).

Useful arylalkenyl groups include any of the above-mentioned C₂₋₆alkenyl groups substituted by any of the above-mentioned aryl groups(e.g., phenylethenyl).

Useful arylalkynyl groups include any of the above-mentioned C₂₋₆alkynyl groups substituted by any of the above-mentioned aryl groups(e.g., phenylethynyl).

Useful aralkyloxy or arylalkoxy groups include oxygen substituted by oneof the above-mentioned arylalkyl groups (e.g., benzyloxy).

Useful (arylalkoxy)carbonyl groups include a carbonyl group substitutedby any of the above-mentioned arylalkoxy groups (e.g.,(benzyloxy)carbonyl).

The term “heteroaryl” or “heteroaromatic” as employed herein refers togroups having 5 to 14 ring atoms, with 6, 10 or 14π electrons shared ina cyclic array, and containing carbon atoms and 1, 2, or 3 oxygen,nitrogen and/or sulfur heteroatoms, or 4 nitrogen atoms. In oneembodiment, the heteroaryl group is a 5- to 10-membered heteroarylgroup. Examples of heteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. Typical heteroaryl groups include thienyl (e.g.,thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl(e.g., pyrrol-1-yl, 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl(e.g., imidazol-1-yl, 1H-imidazol-2-yl and 1H-imidazol-4-yl), tetrazolyl(e.g., tetrazol-1-yl and tetrazol-5-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl). A 5-membered heteroaryl can contain up to 4 heteroatoms.A 6-membered heteroaryl can contain up to 3 heteroatoms. Each heteroatomis independently selected from nitrogen, oxygen and sulfur.

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups preferably one of the C₁₋₆ alkyl groups, and morepreferably one of the C₁₋₄ alkyl groups, substituted by any of theabove-mentioned heteroaryl groups (e.g., (thien-2-yl)methyl,2-furylmethyl, (pyrrol-1-yl)methyl, and 2-(1H-pyrrol-2-yl)ethyl).

Useful heteroarylalkoxy groups include oxygen substituted by one of theabove-mentioned heteroaryl groups.

Useful (heteroarylalkoxy)carbonyl groups include a carbonyl groupsubstituted by any of the above-mentioned heteroarylalkoxy groups.

The terms “heterocyclic” and “heterocyclo” are used herein to meansaturated or partially unsaturated 3-7 membered monocyclic, or 7-10membered bicyclic ring system, which consist of carbon atoms and fromone to four heteroatoms independently selected from the group consistingof O, N, and S, wherein the nitrogen and sulfur heteroatoms can beoptionally oxidized, the nitrogen can be optionally quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on a carbon atom or on a nitrogenatom if the resulting compound is stable. In one embodiment, the 3- to7-membered monocyclic heterocyclic ring is either a saturated, orunsaturated non-aromatic ring. A 3-membered heterocyclo contains 1heteroatom, a 4-membered heterocyclo can contain up to 2 heteroatoms, a5-membered heterocyclo can contain up to 4 heteroatoms, a 6-memberedheterocyclo can contain up to 4 heteroatoms, and a 7-memberedheterocyclo can contain up to 5 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 3- to 7-memberedheterocyclo can be attached via a nitrogen or carbon atom. A 7- to10-membered bicyclic heterocyclo contains from 1 to 4 heteroatomsindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 7- to 10-memberedbicyclic heterocyclo can be attached via a nitrogen or carbon atom.Examples of the heterocyclic rings include, but are not limited to,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxooxazolidinyl,tetrahydrothienyl, imidazolidinyl, hexahydropyrimidinyl, andbenzodiazepines.

Useful (heterocyclo)alkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by any of the above-mentioned heterocyclic groups(e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-1-yl)methyl,(piperidin-1-yl)methyl, (morpholin-4-yl)methyl,(2-oxooxazolidin-4-yl)methyl, 2-(2-oxooxazolidin-4-yl)ethyl,(2-oxo-imidazolidin-1-yl)methyl, (2-oxo-imidazolidin-1-yl)ethyl, and(2-oxo-imidazolidin-1-yl)propyl).

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ cycloalkylgroups, substituted with one or more amino group.

Useful alkylamino and dialkylamino groups are —NHR¹⁸ and —NR¹⁸R¹⁹,respectively, wherein R¹⁸ and R¹⁹ are each independently selected from aC₁₋₁₀ alkyl group, preferably a C₁₋₆ alkyl group, and more preferably aC₁₋₄ alkyl group.

As used herein, the term “aminocarbonyl” refers to —C(═O)NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(═O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful alkoxycarbonyl groups include a carbonyl group substituted by anyof the above-mentioned alkoxy groups (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, iso-butoxycarbonyl, sec-butoxycarbonyl, andpentyloxycarbonyl).

Useful arylcarbonyl groups include a carbonyl group substituted by anyof the above-mentioned aryl groups (e.g., benzoyl).

Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted byone of the above-mentioned alkylcarbonyl groups.

Useful alkylcarbonylamino or acylamino groups include any of theabove-mentioned alkylcarbonyl groups attached to an amino nitrogen, suchas methylcarbonylamino.

As used herein, the term “carboxamido” refers to a radical of formula—C(═O)NR²⁰R²¹, wherein R²⁰ and R²¹ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary carboxamido groups include —CONH₂, —CON(H)CH₃, —CON(CH₃)₂, and—CON(H)Ph.

Useful alkylaminocarbonyl and dialkylaminocarbonyl groups are any of theabove-mentioned carboxamido groups, where R²⁰ is H and R²¹ is C₁₋₁₀alkyl or where R²⁰ and R²¹ are each independently selected from a C₁₋₁₀alkyl group, respectively.

As used herein, the term “sulfonamido” refers to a radical of formula—SO₂NR²²R²³, wherein R²² and R²³ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, and—SO₂N(H)Ph.

As used herein, the term “thiol” refers to —SH.

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by —COOH.

As used herein, the terms “hydroxyl” or “hydroxy” refer to —OH.

As used herein, the term “cyano” refers to —CN.

As used herein, the term “nitro” refers to —NO₂.

As used herein, the term “ureido” refers to —NH—C(═O)—NH₂.

As used herein, the term “azido” refers to —N₃.

The term “ambient temperature” as used herein means the temperature ofthe surroundings. The ambient temperature indoors is the same as roomtemperature, which is from about 20° C. to about 25° C.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment. Typically, the term “about” includes therecited number ±10%. Thus, “about 10” means 9 to 11.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, typically 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl,aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar(C₁₋₆)alkyloxy,carboxamido, sulfonamido, azido, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy, carboxy,aminocarbonyl, (═O), and mercapto(C₁₋₆)alkyl groups mentioned above.Preferred optional substituents include halo, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, halo(C₁₋₆)alkoxy, and amino.

The morphinan scaffold has the following numbering:

Accordingly, substituents R⁶ and R⁷ are at the 10-position in a compoundof any one of Formulae I-XVII.

Compounds of the Invention encompass all the salts of the disclosedcompounds of Formulae I-XVII. The present invention preferably includesall non-toxic pharmaceutically acceptable salts thereof of the disclosedcompounds. Examples of pharmaceutically acceptable addition saltsinclude inorganic and organic acid addition salts and basic salts. Thepharmaceutically acceptable salts include, but are not limited to, metalsalts such as sodium salt, potassium salt, cesium salt and the like;alkaline earth metals such as calcium salt, magnesium salt and the like;organic amine salts such as triethylamine salt, pyridine salt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, phosphate, sulphate and the like;organic acid salts such as citrate, lactate, tartrate, maleate,fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,oxalate, formate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate and the like; and amino acid saltssuch as arginate, asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

Compounds of the Invention also encompass solvates of any of thedisclosed compounds of Formulae I-XVII. Solvates typically do notsignificantly alter the physiological activity or toxicity of thecompounds, and as such may function as pharmacological equivalents. Theterm “solvate” as used herein is a combination, physical associationand/or solvation of a compound of the present invention with a solventmolecule such as, e.g. a disolvate, monosolvate or hemisolvate, wherethe ratio of solvent molecule to compound of the present invention isabout 2:1, about 1:1 or about 1:2, respectively. This physicalassociation involves varying degrees of ionic and covalent bonding,including hydrogen bonding. In certain instances, the solvate can beisolated, such as when one or more solvent molecules are incorporatedinto the crystal lattice of a crystalline solid. Thus, “solvate”encompasses both solution-phase and isolatable solvates. Compounds ofthe Invention may be present as solvated forms with a pharmaceuticallyacceptable solvent, such as water, methanol, ethanol, and the like, andit is intended that the invention includes both solvated and unsolvatedforms of compounds of any of Formulae I-XVII. One type of solvate is ahydrate. A “hydrate” relates to a particular subgroup of solvates wherethe solvent molecule is water. Solvates typically can function aspharmacological equivalents. Preparation of solvates is known in theart. See, for example, M. Caira et al., J. Pharmaceut. Sci.,93(3):601-611 (2004), which describes the preparation of solvates offluconazole with ethyl acetate and with water. Similar preparation ofsolvates, hemisolvates, hydrates, and the like are described by E. C.van Tonder et al., AAPS Pharm. Sci. Tech., 5(1): Article 12 (2004), andA. L. Bingham et al., Chem. Commun.: 603-604 (2001). A typical,non-limiting, process of preparing a solvate would involve dissolving acompound of any of Formulae I-XVII in a desired solvent (organic, water,or a mixture thereof) at temperatures above about 20° C. to about 25°C., then cooling the solution at a rate sufficient to form crystals, andisolating the crystals by known methods, e.g., filtration. Analyticaltechniques such as infrared spectroscopy can be used to confirm thepresence of the solvent in a crystal of the solvate.

Compounds of the Invention can be isotopically-labeled (i.e.,radio-labeled). Examples of isotopes that can be incorporated into thedisclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³²S, ¹⁸F and ³⁶Cl, respectively, andpreferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeled Compounds of theInvention can be prepared by methods known in the art in view of thisdisclosure. For example, tritiated Compounds of the Invention can beprepared by introducing tritium into the particular compound bycatalytic dehalogenation with tritium. This method may include reactinga suitable halogen-substituted precursor of a Compound of the Inventionwith tritium gas in the presence of an appropriate catalyst such as Pd/Cin the presence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

Isotopically labeled Compounds of the Invention, as well as thepharmaceutically acceptable salts and solvates thereof, can be used asradioligands to test for the binding of compounds to an opioid receptor.For example, a radio-labeled Compound of the Invention can be used tocharacterize specific binding of a test or candidate compound to thereceptor. Binding assays utilizing such radio-labeled compounds canprovide an in vitro alternative to animal testing for the evaluation ofchemical structure-activity relationships. For example, the receptorassay may be performed at a fixed concentration of a radiolabeledCompound of the Invention and at increasing concentrations of a testcompound in a competition assay. In a non-limiting embodiment, thepresent invention provides a method for screening a candidate compoundfor the ability to bind to an opioid receptor, comprising a) introducinga fixed concentration of a radio-labeled Compound of the Invention tothe receptor under conditions that permit binding of the radio-labeledcompound to the receptor to form a complex; b) titrating the complexwith a candidate compound; and c) determining the binding of thecandidate compound to said receptor.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms, such as epimers. The present inventionis meant to encompass the uses of all such possible forms, as well astheir racemic and resolved forms and mixtures thereof. The individualenantiomers may be separated according to methods known to those ofordinary skill in the art in view of the present disclosure. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that they include both E and Z geometric isomers. All tautomersare intended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “epimer” refers to diastereomers that have oppositeconfiguration at only one of two or more tetrahedral streogenic centrespresent in the respective molecular entities.

The term “stereogenic center” is an atom, bearing groups such that aninterchanging of any two groups leads to a stereoisomer.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treating” or “treatment” refers to administering a therapy inan amount, manner, or mode effective to improve a condition, symptom, orparameter associated with a disorder or to prevent progression of adisorder, to either a statistically significant degree or to a degreedetectable to one skilled in the art. An effective amount, manner, ormode can vary depending on the subject and may be tailored to thepatient.

Open terms such as “include,” “including,” “contain,” “containing” andthe like mean “comprising.”

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to receptors and are only partly effective asagonists are defined as “partial agonists”. Compounds that bind to areceptor but produce no regulatory effect, but rather block the bindingof ligands to the receptor are defined as “antagonists”. (Ross andKenakin, “Ch. 2: Pharmacodynamics: Mechanisms of Drug Action and theRelationship Between Drug Concentration and Effect”, pp. 31-32, inGoodman & Gilman's the Pharmacological Basis of Therapeutics, 10^(th)Ed. (J. G. Hardman, L. E. Limbird and A. Goodman-Gilman eds., 2001)).

In certain embodiments, the Compound of the Invention is an agonist atone or more of the μ, δ and/or κ opioid receptors. In certainnon-limiting embodiments, the Compound of the Invention produces fewerside effects and/or less severe side effects than currently availableanalgesic opioid compounds when administered at doses producingequivalent levels of analgesia and/or anti-hyperalgesia. In certainembodiments, the Compound of the Invention is an agonist at ORL-1 opioidreceptor.

In certain embodiments, Compounds of the Invention can be used incombination with at least one other therapeutic agent. The othertherapeutic agent can be, but is not limited to, μ-opioid agonist, anon-opioid analgesic, a non-steroidal anti-inflammatory agent, a Cox-IIinhibitor, an anti-emetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca²⁺-channel blocker, an anticancer agent, or amixture thereof.

Compounds of the Invention potently bind to the μ and/or κ and/or δand/or ORL-1 opioid receptors. Compounds of the Invention can bemodulators at the μ and/or κ and/or δ and/or ORL-1 opioid receptors, andtherefore Compounds of the Invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, Compounds of the Invention are antagonists of oneor more opioid receptors. In another embodiment, Compounds of theInvention are antagonists of the μ and/or κ opioid receptors.

In some embodiments, Compounds of the Invention are partial agonists ofone or more opioid receptors. In another embodiment, Compounds of theInvention are partial agonists of the μ and/or κ opioid receptors.

In another embodiment, Compounds of the Invention are agonists of one ormore opioid receptors. In another embodiment, Compounds of the Inventionare agonists of the μ and/or κ opioid receptors.

In some embodiments, Compounds of the Invention have both: (i)antagonist activity at the ORL-1 receptor; and (ii) agonist activity atone or more of the μ, δ and/or κ receptors. In another embodiment,Compounds of the Invention have both: (i) antagonist activity at theORL-1 receptor; and (ii) agonist activity at the receptor. In anotherembodiment, Compounds of the Invention have both: (i) antagonistactivity at the receptor; and (ii) agonist activity at the κ receptor.In another embodiment, Compounds of the Invention have: (i) antagonistactivity at the ORL-1 receptor; (ii) antagonist activity at the μreceptor; and (iii) agonist activity at the κ receptor. In anotherembodiment, Compounds of the Invention have: (i) antagonist activity atthe g receptor; (ii) agonist activity at the κ receptor; and (iii)antagonist activity at the δ receptor.

Compounds of the Invention that are antagonists of the μ-opioid receptoror agonists of κ-opioid receptor, or both, can be used/administered totreat or ameliorate constipation. Compounds of the Invention that areagonists of μ-opioid receptor can be used/administered to treat orameliorate diarrhea.

Compounds of the Invention can be used to treat or prevent acute,chronic pain (which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain), or surgical pain. Examplesof pain that can be treated or prevented using a Compound of theInvention include, but are not limited to, cancer pain, neuropathicpain, labor pain, myocardial infarction pain, pancreatic pain, colicpain, post-operative pain, headache pain, muscle pain, arthritic pain,and pain associated with a periodontal disease, including gingivitis andperiodontitis.

Acute pain includes, but is not limited to, perioperative pain,postoperative pain, post-traumatic pain, acute disease related pain, andpain related to diagnostic procedures, orthopedic manipulations, andmyocardial infarction. Acute pain in the perioperative setting includespain because of pre-existing disease, the surgical procedure, e.g.,associated drains, chest or nasogastric tubes, or complications, or acombination of disease-related and procedure-related sources.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Compounds of the Invention can be used to treat or prevent painassociated with inflammation or with an inflammatory disease in apatient. Such pain can arise where there is an inflammation of the bodytissue which can be a local inflammatory response or a systemicinflammation. For example, a Compound of the Invention can be used totreat or prevent pain associated with inflammatory diseases including,but not limited to, organ transplant rejection; reoxygenation injuryresulting from organ transplantation (see Grupp et al., J. Mol, CellCardiol. 31:297-303 (1999)) including, but not limited to,transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases, such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung diseases, such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory diseasesof the eye, including corneal dystrophy, trachoma, onchocerciasis,uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory disease of the gum, including gingivitis and periodontitis;tuberculosis; leprosy; inflammatory diseases of the kidney, includinguremic complications, glomerulonephritis and nephrosis; inflammatorydisease of the skin, including sclerodermatitis, psoriasis and eczema;inflammatory diseases of the central nervous system, including chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimer's disease, infectiousmeningitis, encephalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis; autoimmune diseases, including Type I and Type II diabetesmellitus; diabetic complications, including, but not limited to,diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), gangrene of thefeet, atherosclerotic coronary arterial disease, peripheral arterialdisease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, jointproblems, and a skin or mucous membrane complication (such as aninfection, a shin spot, a candidal infection or necrobiosis lipoidicadiabeticorum), immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory disease of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andartherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. Compounds ofthe Invention can also be used to treat or prevent pain associated withinflammatory disease that can, for example, be a systemic inflammationof the body, exemplified by gram-positive or gram negative shock,hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent that is administered as a treatmentfor cancer.

Compounds of the Invention can be used to treat or prevent painassociated with nerve injury (i.e., neuropathic pain). Chronicneuropathic pain is a heterogenous disease state with an unclearetiology. In chronic pain, the pain can be mediated by multiplemechanisms. This type of pain generally arises from injury to theperipheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. The chronic pain is differentfrom acute pain in that chronic neuropathic pain patients suffer theabnormal pain sensations that can be described as spontaneous pain,continuous superficial burning and/or deep aching pain. The pain can beevoked by heat-, cold-, and mechano-hyperalgesia or by heat-, cold-, ormechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinalcord injury can also induce neuropathic pain. Cancer-related neuropathicpain results from tumor growth compression of adjacent nerves, brain, orspinal cord. In addition, cancer treatments, including chemotherapy andradiation therapy, can cause nerve injury. Neuropathic pain includes butis not limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

Compounds of the Invention can be used to treat or prevent painassociated with migraine including, but not limited to, migraine withoutaura (“common migraine”), migraine with aura (“classic migraine”),migraine without headache, basilar migraine, familial hemiplegicmigraine, migrainous infarction, and migraine with prolonged aura.

Compounds of the Invention can also be used as an agent to treat orprevent withdrawal from alcohol addiction or drug addiction; as an agentto treat or prevent addictive disorders; as an agent to treat a pruriticcondition; and in treating or ameliorating constipation and diarrhea.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XVI, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicamentfor treating a disorder responsive to the modulation of one or moreopioids receptors (e.g., any of the disorders listed above) in a patientsuffering from said disorder.

Furthermore, the present invention is directed to a method ofmodulating, in particular activating, one or more opioid receptors in apatient in need thereof, said method comprising administering to thepatient at least one compound represented by any of defined FormulaeI-XVI, or a pharmaceutically acceptable salt or solvate thereof.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XVI, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicament,in particular a medicament for modulating, in particular activating, oneor more opioid receptors, in a patient in need thereof.

Synthesis of Compounds

Compounds of the Invention can be prepared using methods known to thoseskilled in the art in view of this disclosure, or by illustrativemethods shown in the schemes below. For example, compounds of FormulaeI-XVI can be prepared as shown in the Schemes A-H below. Additionalmethods of synthesis are described and illustrated in the workingexamples set forth below.

Compound A is converted to Compound B by treatment with a suitablesource of ammonia, such as (NH₄)₂CO₃, and a suitable cyanide, such asKCN, in a suitable solvent, such as aq. EtOH. Compound B is oxidized toCompound C by reaction with a suitable reagent, such as CrO₃ in diluteH₂SO₄ or KMnO₄ and MgSO₄ in a mixture of t-BuOH and pyridine. Compound Cis reduced to Compound D by reaction with a suitable reducing agent,such as NaBH₄, in a suitable solvent, such as MeOH or EtOH. Compound Dis converted to Compound E by treatment with a suitable fluorinatingagent, such as DAST, in a suitable solvent, such as DCM. Compound A canbe prepared as described in, for example, Nagase, H., et al., J. Org.Chem., 2011, 76, 2257.

Compound F is converted to Compound G by treatment with a suitablereagent, such as BBr₃, in a suitable solvent, such as DCM.

Compound H is converted to Compound I by treatment with a suitablesource of ammonia, such as (NH₄)₂CO₃, and a suitable cyanide, such asKCN, in a suitable solvent, such as aq. EtOH. Compound I is oxidized toCompound J by reaction with a suitable reagent, such as CrO₃ in diluteH₂SO₄ or KMnO₄ and MgSO₄ in a mixture of t-BuOH and pyridine. Compound Jis reduced to Compound K by reaction with a suitable reducing agent,such as NaBH₄, in a suitable solvent, such as MeOH or EtOH. Compound Kis converted to Compound L by treatment with a suitable fluorinatingagent, such as DAST in a suitable solvent, such as DCM.

The starting Compound H, and specifically Compound H′:

can be prepared, for example, as described in Hupp C. D., et al.,Tetrahedron Letters 51:2359-2361 (2010) and Ida Y., et al., Bioorganic &Medical Chemistry 20:949-961 (2012). Compounds having the oppositeisomer with respect to R³ can be prepared, for example, as described inPolazzi J. O. et al., J. Med. Chem. 23:174-179 (1980).

Compound M is converted to Compound N by treatment with a suitablereagent, such as BBr₃, in a suitable solvent, such as DCM.

Subsequent side chain modifications can be accomplished via appropriatefunctional group manipulations known to one skilled in the art.

Compounds of the invention, where R⁴ and/or R⁵ is other than hydrogencan be prepared as described in Scheme E.

In Scheme E, R¹-R⁷ are as described for Formula I and R¹ is R⁵ or anamine protecting group. X is halogen, such as chlorine or bromine, andthe base can be a weaker base such as, for example, potassium carbonate(K₂CO₃). The stronger base can be, for example, sodium hydride (NaH).Suitable amine protecting groups include, for example, a benzyl (Bn)group. Further suitable amine protecting groups can be found, forexample, in Wuts, P. G. M. & Greene, T. W., Greene's Protective Groupsin Organic Synthesis, 4rd Ed. (J. Wiley & Sons, 2007).

Compounds of the Invention, where R⁴ and R⁵ are both the same and otherthan hydrogen can be prepared as described in Scheme F.

In Scheme F, R¹-R³, R⁶ and R⁷ are as defined for Formula I, and R″ is asdefined for R⁴ and R⁵ and is other than hydrogen. X is halogen and thestronger base can be as defined above in Scheme E.

Compound O is converted to Compound P by treatment with a suitablehalide, such as an iodide, wherein R′″ is an optionally substituted arylor heteroaryl, in the presence of a suitable copper salt, such as copper(I) iodide, and a suitable base, such as K₂CO₃, in a suitable solvent,such as aq. DMF.

The opposite isomers of the compounds described in Schemes C-G can beprepared starting from compound H″:

Compound H″ can be prepared according methods described in the art, suchas, for example, in US 2009/0156818, US 2009/0156820, and Hupp C. D., etal. (supra). Accordingly, for example, compound of Formula H″, where R¹is OMe and R² is cyclopropylmethyl, can be prepared as described inScheme H starting from CAS#6080-33-7:

In vitro Assay Protocols

μ-Opioid Receptor Binding Assay Procedures: Radioliganddose-displacement binding assays for μ-opioid receptors used 0.3 nM[³H]-diprenorphine (Perkin Elmer, Shelton, Conn.), with 5 mg membraneprotein/well in a final volume of 500 μl binding buffer (10 mM MgCl₂, 1mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were carried out inthe absence or presence of increasing concentrations of unlabelednaloxone. All reactions were conducted in 96-deep well polypropyleneplates for 2 hours at room temperature. Binding reactions wereterminated by rapid filtration onto 96-well Unifilter GF/C filter plates(Perkin Elmer, Shelton, Conn.), presoaked in 0.5% polyethylenimine usinga 96-well tissue harvester (Perkin Elmer, Shelton, Conn.) followed byperforming three filtration washes with 500 μl of ice-cold bindingbuffer. Filter plates were subsequently dried at 50° C. for 2-3 hours.BetaScint scintillation cocktail (Perkin Elmer, Shelton, Conn.) wasadded (50 μl/well), and plates were counted using a Packard Top-Countfor 1 min/well. The data were analyzed using the one-site competitioncurve fitting functions in GraphPad PRISM™ v. 3.0 or higher (San Diego,Calif.), or an in-house function for one-site competition curve-fitting.

μ-Opioid Receptor Binding Data:

Generally, the lower the K_(i) value, the more effective Compounds ofthe Invention will be at treating or preventing pain or anotherCondition. In certain embodiments, Compounds of the Invention exhibit aK_(i)(nM) of about 10,000 or less for binding to μ-opioid receptors.Typically, Compounds of the Invention exhibit a K_(i)(nM) of about 1000or less for binding to μ-opioid receptors. In one embodiment, Compoundsof the Invention exhibit a K_(i) (nM) of about 300 or less for bindingto μ-opioid receptors. In another embodiment, Compounds of the Inventionexhibit a K_(i) (nM) of about 100 or less for binding to μ-opioidreceptors. In another embodiment, Compounds of the Invention exhibit aK_(i)(nM) of about 10 or less for binding to μ-opioid receptors. Instill another embodiment, Compounds of the Invention exhibit a K_(i)(nM) of about 1 or less for binding to μ-opioid receptors. In stillanother embodiment, Compounds of the Invention exhibit a K_(i) (nM) ofabout 0.1 or less for binding to μ-opioid receptors.

μ-Opioid Receptor Functional Assay Procedures:

[³⁵S]GTPγS functional assays were conducted using freshly thawedμ-receptor membranes prepared in-house from a cell line expressingrecombinant μ opioid receptor in a HEK-293, CHO or U-2 OS cellbackground, or purchased from a commercial source (Perkin Elmer,Shelton, Conn.; or DiscovRx, Fremont, Calif.). Assay reactions wereprepared by sequentially adding the following reagents to binding buffer(100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice (finalconcentrations indicated): membrane protein (0.026 mg/mL), saponin (10mg/mL), GDP (3 mM) and [³⁵S]GTPγS (0.20 nM; Perkin Elmer, Shelton,Conn.). The prepared membrane solution (190 l/well) was transferred to96-shallow well polypropylene plates containing 10 μl of 20×concentrated stock solutions of the agonist [D-Ala², N-methyl-Phe⁴Gly-ol⁵]-enkephalin (DAMGO) prepared in dimethyl sulfoxide (DMSO).Plates were incubated for 30 min at about 25° C. with shaking. Reactionswere terminated by rapid filtration onto 96-well Unifilter GF/B filterplates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester(Perkin Elmer, Shelton, Conn.) followed by three filtration washes with200 μl of ice-cold wash buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4).Filter plates were subsequently dried at 50° C. for 2-3 hours. BetaScintscintillation cocktail (Perkin Elmer, Shelton, Conn.) was added (50μl/well) and plates were counted using a Packard Top-Count for 1min/well. Data were analyzed using the sigmoidal dose-response curvefitting functions in GraphPad PRISM v. 3.0, or an in-house function fornon-linear, sigmoidal dose-response curve-fitting.

μ-Opioid Receptor Functional Data:

GTP EC₅₀ is the concentration of a compound providing 50% of the maximalresponse for the compound at a μ-opioid receptor. Typically, Compoundsof the Invention exhibit a μ GTP EC₅₀ (nM) of about 5000 or less. Incertain embodiments, Compounds of the Invention exhibit a μ GTP EC₅₀(nM) of about 2000 or less; or about 1000 or less; or about 100 or less;or about 10 or less; or about 1 or less; or about 0.1 or less.

μ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by DAMGO, a standard μ agonist. Generally, the μGTP E_(max) (%) value measures the efficacy of a compound to treat orprevent pain or other Conditions. Typically, Compounds of the Inventionexhibit a μ GTP E_(max) (%) of greater than about 10%; or greater thanabout 20%. In certain embodiments, Compounds of the Invention exhibit aμ GTP E_(max) (%) of greater than about 50%; or greater than about 65%;or greater than about 75%; or greater than about 85%; or greater thanabout 100%.

κ-Opioid Receptor Binding Assay Procedures:

Membranes from HEK-293 cells, CHO or U-2 OS cells expressing therecombinant human κ opioid receptor (κ) were prepared by lysing cells inice cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10cm dish) followed by homogenization with a tissue grinder/Teflon pestle.Membranes from a cell line naturally expressing kappa opioid receptorcan also be used. Membranes were collected by centrifugation at 30,000×gfor 15 min at 4° C. and pellets were resuspended in hypotonic buffer toa final concentration of 1-3 mg/mL. Protein concentrations weredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of K receptor membranes were stored at−80° C.

Radioligand dose displacement assays used 0.4 nM [³H]-U69,593 (GEHealthcare, Piscataway, N.J.; 40 Ci/mmole) with 15 μg membrane protein(recombinant κ opioid receptor expressed in HEK 293 cells; in-houseprep) in a final volume of 200 μl binding buffer (5% DMSO, 50 mM Trizmabase, pH 7.4). Non-specific binding was determined in the presence of 10μM unlabeled naloxone or U69,593. All reactions were performed in96-well polypropylene plates for 1 hour at a temperature of about 25° C.Binding reactions were terminated by rapid filtration onto 96-wellUnifilter GF/C filter plates (Perkin Elmer, Shelton, Conn.) presoaked in0.5% polyethylenimine (Sigma). Harvesting was performed using a 96-welltissue harvester (Perkin Elmer, Shelton, Conn.) followed by fivefiltration washes with 200 μl ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 1-2 hours. Fifty μl/wellscintillation cocktail (Perkin Elmer, Shelton, Conn.) was added andplates were counted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Binding Data:

In certain embodiments, Compounds of the Invention exhibit a K_(i) (nM)for κ receptors of about 10,000 or more (which, for purposes of thisinvention, is interpreted as having no binding to the κ receptors).Certain Compounds of the Invention exhibit a K_(i) (nM) of about 20,000or less for κ receptors. In certain embodiments, Compounds of theInvention exhibit a K_(i) (nM) of about 10,000 or less; or about 5000 orless; or about 1000 or less; or about 500 or less; or about 450 or less;or about 350 or less; or about 200 or less; or about 100 or less; orabout 50 or less; or about 10 or less; or about 1 or less; or about 0.1or less for κ receptors.

κ-Opioid Receptor Functional Assay Procedures:

Functional [³⁵S]GTPγS binding assays were conducted as follows. κ opioidreceptor membrane solution was prepared by sequentially adding finalconcentrations of 0.026 μg/μl κ membrane protein (in-house), 10 μg/mLsaponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl,10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution(190 μl/well) was transferred to 96-shallow well polypropylene platescontaining 10 μl of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at a temperature of about 25°C. with shaking. Reactions were terminated by rapid filtration onto96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.)using a 96-well tissue harvester (Packard) and followed by threefiltration washes with 200 μl ice-cold binding buffer (10 mM NaH₂PO₄, 10mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50° C. for2-3 hours. Fifty μl/well scintillation cocktail (Perkin Elmer, Shelton,Conn.) was added and plates were counted in a Packard Top-Count for 1min/well.

κ-Opioid Receptor Functional Data:

κ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a K receptor. Certain Compounds ofthe Invention exhibit a κ GTP EC₅₀ (nM) of about 20,000 or less tostimulate κ opioid receptor function. In certain embodiments, Compoundsof the Invention exhibit a κ GTP EC₅₀ (nM) of about 10,000 or less; orabout 5000 or less; or about 2000 or less; or about 1500 or less; orabout 1000 or less; or about 600 or less; or about 100 or less; or about50 or less; or about 25 or less; or about 10 or less; or about 1 orless; or about 0.1 or less.

κ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by U69,593. Certain Compounds of the Inventionexhibit a κ GTP E_(max) (%) of greater than about 1%; or greater thanabout 5%; or greater than about 10%; or greater than about 20%. Incertain embodiments, Compounds of the Invention exhibit a κ GTP E_(max)(%) of greater than about 50%; or greater than about 75%; or greaterthan about 90%; or greater than about 100%.

δ-Opioid Receptor Binding Assay Procedures:

δ-Opioid Receptor Binding Assay Procedures can be conducted as follows.Radioligand dose-displacement assays use 0.3 nM [³H]-Naltrindole (PerkinElmer, Shelton, Conn.; 33.0 Ci/mmole) with 5 g membrane protein (PerkinElmer, Shelton, Conn.) in a final volume of 500 μl binding buffer (5 mMMgCl₂, 5% DMSO, 50 mM Trizma base, pH 7.4). Non-specific binding isdetermined in the presence of 25 μM unlabeled naloxone. All reactionsare performed in 96-deep well polypropylene plates for 1 hour at atemperature of about 25° C. Binding reactions are terminated by rapidfiltration onto 96-well Unifilter GF/C filter plates (Perkin Elmer,Shelton, Conn.) presoaked in 0.5% polyethylenimine (Sigma). Harvestingis performed using a 96-well tissue harvester (Perkin Elmer, Shelton,Conn.) followed by five filtration washes with 500 μl ice-cold bindingbuffer. Filter plates are subsequently dried at 50° C. for 1-2 hours.Fifty μl/well scintillation cocktail (Perkin Elmer, Shelton, Conn.) isadded and plates are counted in a Packard Top-Count for 1 min/well.

δ-Opioid Receptor Binding Data:

In certain embodiments, Compounds of the Invention can exhibit a K_(i)(nM) for δ receptors of about 10,000 or more (which, for the purposes ofthis invention, is interpreted as having no binding to the δ receptors).Certain Compounds of the Invention can exhibit a K_(i) (nM) of about20,000 or less for δ receptors. In one embodiment, Compounds of theInvention can exhibit a Ki (nM) of about 10,000 or less; or of about9000 or less for δ receptors. In another embodiment, Compounds of theInvention can exhibit a K_(i) (nM) of about 7500 or less; or of about6500 or less; or of about 5000 or less; or of about 3000 or less; or ofabout 2500 or less for δ receptors. In another embodiment, Compounds ofthe Invention can exhibit a K_(i)(nM) of about 1000 or less; or of about500 or less; or of about 350 or less; or of about 250 or less; or ofabout 100 or less; or of about 10 or less for δ receptors.

δ-Opioid Receptor Functional Assay Procedures:

Functional [³⁵S]GTPγS binding assays can be conducted as follows. δopioid receptor membrane solution is prepared by sequentially addingfinal concentrations of 0.026 μg/l δ membrane protein (Perkin Elmer,Shelton, Conn.), 10 μg/mL saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS tobinding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice.The prepared membrane solution (190 μl/well) is transferred to96-shallow well polypropylene plates containing 10 μl of 20×concentrated stock solutions of agonist prepared in DMSO. Plates areincubated for 30 min at a temperature of about 25° C. with shaking.Reactions are terminated by rapid filtration onto 96-well Unifilter GF/Bfilter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissueharvester (Packard) and followed by three filtration washes with 200 μlice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filterplates are subsequently dried at 50° C. for 1-2 hours. Fifty μl/wellscintillation cocktail (Perkin Elmer, Shelton, Conn.) is added andplates are counted in a Packard Top-count for 1 min/well.

δ-Opioid Receptor Functional Data:

δ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a δ receptor. Certain Compounds ofthe Invention can exhibit a δ GTP EC₅₀ (nM) of about 20,000 or less; orabout 10,000 or less. In certain embodiments, Compounds of the Inventioncan exhibit a δ GTP EC₅₀ (nM) of about 3500 or less; or of about 1000 orless; or of about 500 or less; or of about 100 or less; or of about 90or less; or of about 50 or less; or of about 25 or less; or of about 10or less.

δ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by met-enkephalin. Certain Compounds of theInvention can exhibit a δ GTP E_(max) (%) of greater than about 1%; orof greater than about 5%; or of greater than about 10%. In oneembodiment, Compounds of the Invention can exhibit a δ GTP E_(max) (%)of greater than about 30%. In another embodiment, Compounds of theInvention can exhibit a δ GTP E_(max) (%) of greater than about 50%; orof greater than about 75%; or of greater than about 90%. In anotherembodiment, Compounds of the Invention exhibit a δ GTP E_(max) (%) ofgreater than about 100%.

ORL-1 Receptor Binding Assay Procedure:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like receptor (ORL-1) (Perkin Elmer, Shelton, Conn.) can beprepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with atissue grinder/Teflon pestle. Membranes are collected by centrifugationat 30,000×g for 15 min at 4° C. and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrations aredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes are storedat −80° C.

Radioligand binding assays (screening and dose-displacement) use 0.1 nM[³H]-nociceptin (Perkin Elmer, Shelton, Conn.; 87.7 Ci/mmole) with 12 gmembrane protein in a final volume of 500 μl binding buffer (10 mMMgCl₂, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Non-specific binding isdetermined in the presence of 10 nM unlabeled nociceptin (AmericanPeptide Company). All reactions are performed in 96-deep wellpolypropylene plates for 1 h at room temperature. Binding reactions areterminated by rapid filtration onto 96-well Unifilter GF/C filter plates(Perkin Elmer, Shelton, Conn.) presoaked in 0.5% polyethylenimine(Sigma). Harvesting is performed using a 96-well tissue harvester(Perkin Elmer, Shelton, Conn.) followed by three filtration washes with500 μl ice-cold binding buffer. Filter plates are subsequently dried at50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (PerkinElmer, Shelton, Conn.) is added and plates are counted in a PackardTop-Count for 1 min/well. The data from screening and dose-displacementexperiments are analyzed using Microsoft Excel and the curve fittingfunctions in GraphPad PRISM™, v. 3.0 or higher, respectively, or anin-house function for one-site competition curve-fitting.

ORL-1 Receptor Binding Data:

Certain Compounds of the Invention can have a K_(i) (nM) of about 5000or less. In one embodiment, certain Compounds of the Invention can havea K_(i) (nM) of about 1000 or less. In one embodiment, certain Compoundsof the Invention can have a K_(i) (nM) of about 500 or less. In otherembodiments, the Compounds of the Invention can have a K_(i)(nM) ofabout 300 or less; or of about 100 or less; or of about 50 or less; orof about 20 or less. In yet other embodiments, the Compounds of theInvention can have a K_(i)(nM) of about 10 or less; or of about 1 orless; or of about 0.1 or less.

ORL-1 Receptor Functional Assay Procedure:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like (ORL-1) (Perkin Elmer, Shelton, Conn.) can be prepared bylysing cells in ice-cold hypotonic buffer (2.5 mM Mg Cl₂, 50 mM HEPES,pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/Teflon pestle. Membranes are collected by centrifugation at30,000×g for 15 min at 4° C., and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrations aredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes are storedat −80° C.

Functional [³⁵S]GTPγS binding assays are conducted as follows. ORL-1membrane solution is prepared by sequentially adding finalconcentrations of 0.026 μg/μl ORL-1 membrane protein, 10 μg/ml saponin,3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190μl/well) is transferred to 96-shallow well polypropylene platescontaining 10 μl of 20× concentrated stock solutions ofagonist/nociceptin prepared in DMSO. Plates are incubated for 30 min atroom temperature with shaking. Reactions are terminated by rapidfiltration onto 96-well Unifilter GF/B filter plates (Perkin Elmer,Shelton, Conn.) using a 96-well tissue harvester (Packard) and followedby three filtration washes with 200 μl ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates are subsequently dried at50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (PerkinElmer, Shelton, Conn.) is added and plates are counted in a PackardTop-Count for 1 min/well. Data are analyzed using the sigmoidaldose-response curve fitting functions in GraphPad PRISM v. 3.0 orhigher, or an in-house function for non-linear, sigmoidal dose-responsecurve-fitting.

ORL-1 Receptor Functional Data:

ORL-1 GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at an ORL-1 receptor. In certainembodiments, the Compounds of the Invention that have a high bindingaffinity (i.e. low K_(i) value) can have an ORL-1 GTP EC₅₀ (nM) ofgreater than about 10,000 (i.e. will not stimulate at therapeuticconcentrations) In certain embodiments Compounds of the Invention canhave an ORL-1 GTP EC₅₀ (nM) of about 20,000 or less. In one embodiment,the Compounds of the Invention can have an ORL-1 GTP EC₅₀ (nM) of about10,000 or less; or of about 5000 or less; or of about 1000 or less. Instill other embodiments, the Compounds of the Invention can have anORL-1 GTP EC₅₀ (nM) of about 100 or less; or of about 10 or less; or ofabout 1 or less; or of about 0.1 or less.

ORL-1 GTP E_(max) % is the maximal effect elicited by a compoundrelative to the effect elicited by nociceptin, a standard ORL-1 agonist.In certain embodiments, Compounds of the Invention can have an ORL-1 GTPE_(max) of less than 10% (which, for the purposes of this invention, isinterpreted as having antagonist activity at ORL-1 receptors). CertainCompounds of the Invention can have an ORL-1 GTP E_(max) (%) of greaterthan 1%; or of greater than 5%; or of greater than 10%. In otherembodiments, Compounds of the Invention can have an ORL-1 GTP E_(max) ofgreater than 20%; or of greater than 50%; or of greater than 75%; or ofgreater than 88%; or of greater than 100%.

In Vivo Assays for Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a Compound ofthe Invention when food is removed for about 16 hours before dosing. Acontrol group acts as a comparison to rats treated with a Compound ofthe Invention. The control group is administered the carrier for theCompound of the Invention. The volume of carrier administered to thecontrol group is the same as the volume of carrier and Compound of theInvention administered to the test group.

Acute Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of acute pain, the rat tail flick can be used. Rats aregently restrained by hand and the tail exposed to a focused beam ofradiant heat at a point 5 cm from the tip using a tail flick unit (Model7360, commercially available from Ugo Basile of Italy). Tail flicklatencies are defined as the interval between the onset of the thermalstimulus and the flick of the tail. Animals not responding within 20seconds are removed from the tail flick unit and assigned a withdrawallatency of 20 seconds. Tail flick latencies are measured immediatelybefore (pre-treatment) and 1, 3, and 5 hours following administration ofa Compound of the Invention. Data are expressed as tail flick latency(s)and the percentage of the maximal possible effect (% MPE), i.e., 20seconds, is calculated as follows:

${\% \mspace{14mu} {MPE}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \right\rbrack}{\left( {{20\mspace{14mu} s} - {{pre}\text{-}{administration}\mspace{14mu} {latency}}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

To assess the actions of a Compound of the Invention for the treatmentor prevention of acute pain, the rat hot plate test can also be used.Rats are tested using a hot plate apparatus consisting of a clearplexiglass cylinder with a heated metal floor maintained at atemperature of 48-52° C. (Model 7280, commercially available from UgoBasile of Italy). A rat is placed into the cylinder on the hot plateapparatus for a maximum duration of 30 s, or until it exhibits anocifensive behavior (behavioral endpoint), at which time it is removedfrom the hot plate, and the response latency recorded. Hot platelatencies are measured immediately before (pre-treatment) and 1, 3, and5 hours following administration of a Compound of the Invention. Thenocifensive behavioral endpoint is defined as any of the following: 1)paw withdrawal, either as a sustained lift or with shaking or licking;2) alternating foot lifting; 3) excape or attempted escape from thetesting device; or 4) vocalization. Data are expressed as responselatency(s) and the percentage of the maximal possible effect iscalculated as described above for the tail flick test. The hot platetest is described in G. Woolfe and A. D. MacDonald, J. Pharmacol. Exp.Ther. 80:300-307 (1944).

Inflammatory Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of inflammatory pain, the Freund's complete adjuvant(“FCA”) model of inflammatory pain can be used. FCA-induced inflammationof the rat hind paw is associated with the development of persistentinflammatory mechanical hyperalgesia and provides reliable prediction ofthe anti-hyperalgesic action of clinically useful analgesic drugs (L.Bartho et al., “Involvement of Capsaicin-sensitive Neurones inHyperalgesia and Enhanced Opioid Antinociception in Inflammation,”Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). Theleft hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. Prior to injection of FCA (baseline) and 24 hourpost injection, the animal is assessed for response to noxiousmechanical stimuli by determining the PWT, as described below. Rats arethen administered a single injection of 1, 3, or 10 mg/kg of either aCompound of the Invention; 30 mg/kg of a control drug selected fromCelebrex, indomethacin or naproxen; or carrier. Responses to noxiousmechanical stimuli are determined 1, 3, 5 and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

Neuropathic Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of neuropathic pain, either the Seltzer model or the Chungmodel can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration. Percentage reversal ofneuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theInvention. The animal can also be assessed for response to noxiousthermal stimuli or for tactile allodynia, as described below. The Chungmodel for neuropathic pain is described in S. H. Kim, “An ExperimentalModel for Peripheral Neuropathy Produced by Segmental Spinal NerveLigation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia:

The paw pressure assay can be used to assess mechanical hyperalgesia.For this assay, hind paw withdrawal thresholds (PWT) to a noxiousmechanical stimulus are determined using an analgesymeter (Model 7200,commercially available from Ugo Basile of Italy) as described in C.Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). The ratis gently restrained, its hindpaw is placed on a small round platform,and punctate pressure is applied to the dorsal surface of the hindpaw ina graded manner. The maximum weight that is applied to the hind paw isset at 250 g and the end point is taken as complete withdrawal of thepaw. PWT is determined once for each rat at each time point and eitheronly the affected (ipsilateral; same side as the injury) rear paw istested, or both the ipsilateral and contralateral (non-injured; oppositeto the injury) rear paw are tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:

The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulusapplied to the plantar surface of the hindpaw are determined using aplantar test apparatus (commercially available from Ugo Basile of Italy)following the technique described by K. Hargreaves et al., “A New andSensitive Method for Measuring Thermal Nociception in CutaneousHyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposure time is setat 32 seconds to avoid tissue damage and any directed paw withdrawalfrom the heat source is taken as the end point. Three latencies aredetermined at each time point and averaged. Either only the affected(ipsilateral) paw is tested, or both the ipsilateral and contralateral(non-injured) paw are tested.

Assessment of Tactile Allodynia:

To assess tactile allodynia, rats are placed in clear, plexiglasscompartments with a wire mesh floor and allowed to habituate for aperiod of at least 15 minutes. After habituation, a series of von Freymonofilaments are presented to the plantar surface of the affected(ipsilateral) foot of each rat. The series of von Frey monofilamentsconsists of six monofilaments of increasing diameter, with the smallestdiameter fiber presented first. Five trials are conducted with eachfilament with each trial separated by approximately 2 minutes. Eachpresentation lasts for a period of 4-8 seconds or until a nociceptivewithdrawal behavior is observed. Flinching, paw withdrawal or licking ofthe paw are considered nociceptive behavioral responses.

Assessment of Respiratory Depression:

To assess respiratory depression, rats can be prepared by implanting afemoral artery cannula via which blood samples are taken. Blood samplesare taken prior to drug administration, then 1, 3, 5 and 24 hourspost-treatment. Blood samples are processed using an arterial blood gasanalyzer (e.g., IDEXX VetStat with Respiratory/Blood Gas testcartridges). Comparable devices are a standard tool for blood gasanalysis (e.g., D. Torbati et al., Intensive Care Med. (26): 585-591(2000).

Assessment of Gastric Motility.

Animals are treated with vehicle, reference compound or test article byoral gavage at a volume of 10 mL/kg. At one hour post-dose, all animalsare treated with charcoal meal solution (5% non-activated charcoalpowder in a solution of 1% carboxymethylcellulose in water) at a volumeof 10 mL/kg. At two hours post-dose (one hour post-charcoal), animalsare sacrificed by carbon dioxide inhalation or isoflurane overdose andthe transit of charcoal meal identified. The stomach and small intestineare removed carefully and each placed on a saline-soaked absorbentsurface. The distance between the pylorus and the furthest progressionof charcoal meal is measured and compared to the distance between thepylorus and the ileocecal junction. The charcoal meal transit isexpressed as a percentage of small intestinal length traveled.

Pharmaceutical Compositions

Due to their activity, the Compounds of the Invention are advantageouslyuseful in human and veterinary medicine. As described above, theCompounds of the Invention are useful for treating or preventing aCondition in a patient in need thereof. The Compounds of the Inventioncan be administered to any patient requiring modulation of the opioidreceptors. The term “patient” as used herein refers to any animal thatmay experience the beneficial effects of a Compound of the Invention.Foremost such animals are mammals, e.g., humans and companion animals,although the invention is not intended to be so limited.

When administered to a patient, a Compound of the Invention can beadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. A Compound of theInvention can be administered by any appropriate route, as determined bythe medical practitioner. Methods of administration may includeintradermal, intramuscular, intraperitoneal, parenteral, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, buccal,intracerebral, intravaginal, transdermal, transmucosal, rectal, byinhalation, or topical (particularly to the ears, nose, eyes, or skin).Delivery can be either local or systemic. In certain embodiments,administration will result in the release of a Compound of the Inventioninto the bloodstream.

Pharmaceutical compositions of the invention can take the form ofsolutions, suspensions, emulsions, tablets, pills, pellets, powders,multi-particulates, capsules, capsules containing liquids, capsulescontaining powders, capsules containing multi-particulates, lozenges,sustained-release formulations, suppositories, transdermal patches,transmucosal films, sub-lingual tablets or tabs, aerosols, sprays, orany other form suitable for use. In one embodiment, the composition isin the form of a tablet. In another embodiment, the composition is inthe form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical excipients are described inRemington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed.,19th ed. 1995), incorporated herein by reference.

Pharmaceutical compositions of the invention preferably comprise asuitable amount of a pharmaceutically acceptable excipient so as toprovide the form for proper administration to the patient. Such apharmaceutical excipient can be a diluent, suspending agent,solubilizer, binder, disintegrant, preservative, coloring agent,lubricant, and the like. The pharmaceutical excipient can be a liquid,such as water or an oil, including those of petroleum, animal,vegetable, or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil, and the like. The pharmaceutical excipient can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipient is sterile whenadministered to a patient. Water is a particularly useful excipient whena Compound of the Invention is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid excipients, particularly for injectable solutions.Suitable pharmaceutical excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. The inventioncompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986).

In certain embodiments, the Compounds of the Invention are formulatedfor oral administration. A Compound of the Invention to be orallydelivered can be in the form of tablets, capsules, gelcaps, caplets,lozenges, aqueous or oily solutions, suspensions, granules, powders,emulsions, syrups, or elixirs, for example. When a Compound of theInvention is incorporated into oral tablets, such tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, multiply compressed or multiply layered.

An orally administered Compound of the Invention can contain one or moreadditional agents such as, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,and stabilizers, to provide stable, pharmaceutically palatable dosageforms. Techniques and compositions for making solid oral dosage formsare described in Pharmaceutical Dosage Forms: Tablets (Lieberman,Lachman and Schwartz, eds., 2nd ed.) published by Marcel Dekker, Inc.Techniques and compositions for making tablets (compressed and molded),capsules (hard and soft gelatin) and pills are also described inRemington's Pharmaceutical Sciences 1553-1593 (Arthur Osol, ed., 16^(th)ed., Mack Publishing, Easton, Pa. 1980). Liquid oral dosage formsinclude aqueous and nonaqueous solutions, emulsions, suspensions, andsolutions and/or suspensions reconstituted from non-effervescentgranules, optionally containing one or more suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, coloring agents, flavoring agents, and the like. Techniquesand compositions for making liquid oral dosage forms are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger andBanker, eds.) published by Marcel Dekker, Inc.

When a Compound of the Invention is formulated for parenteraladministration by injection (e.g., continuous infusion or bolusinjection), the formulation can be in the form of a suspension,solution, or emulsion in an oily or aqueous vehicle, and suchformulations can further comprise pharmaceutically necessary additivessuch as one or more stabilizing agents, suspending agents, dispersingagents, and the like. When a Compound of the Invention is to be injectedparenterally, it can be, e.g., in the form of an isotonic sterilesolution. A Compound of the Invention can also be in the form of apowder for reconstitution as an injectable formulation.

In certain embodiments, a Compound of the Invention is formulated into apharmaceutical composition for intravenous administration. Typically,such compositions comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent. ACompound of the Invention for intravenous administration can optionallyinclude a local anesthetic such as benzocaine or prilocaine to lessenpain at the site of the injection. Generally, the ingredients aresupplied either separately or mixed together in unit dosage form, forexample, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampule or sachette indicatingthe quantity of active agent. Where a Compound of the Invention is to beadministered by infusion, it can be dispensed, for example, with aninfusion bottle containing sterile pharmaceutical grade water or saline.Where a Compound of the Invention is administered by injection, anampule of sterile water for injection or saline can be provided so thatthe ingredients can be mixed prior to administration.

When a Compound of the Invention is to be administered by inhalation, itcan be formulated into a dry aerosol, or an aqueous or partially aqueoussolution.

In another embodiment, a Compound of the Invention can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); and Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer 317-327 and 353-365 (1989)).

In certain embodiments, a Compound of the Invention is administeredlocally. This can be achieved, for example, by local infusion duringsurgery, topical application, e.g., in conjunction with a wound dressingafter surgery, by injection, by means of a catheter, by means of asuppository or enema, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, a Compound of the Invention can be delivered inan immediate release form. In other embodiments, a Compound of theInvention can be delivered in a controlled-release system orsustained-release system. Controlled- or sustained-releasepharmaceutical compositions can have a common goal of improving drugtherapy over the results achieved by their non-controlled ornon-sustained-release counterparts. In one embodiment, a controlled- orsustained-release composition comprises a minimal amount of a Compoundof the Invention to treat or prevent the Condition (or a symptomthereof) in a minimum amount of time. Advantages of controlled- orsustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased compliance. In addition,controlled- or sustained-release compositions can favorably affect thetime of onset of action or other characteristics, such as blood levelsof the Compound of the Invention, and can thus reduce the occurrence ofadverse side effects.

Controlled- or sustained-release compositions can initially immediatelyrelease an amount of a Compound of the Invention that promptly producesthe desired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the Compound of the Invention tomaintain a level of therapeutic or prophylactic effect over an extendedperiod of time. To maintain a constant level of the Compound of theInvention in the body, the Compound of the Invention can be releasedfrom the dosage form at a rate that will replace the amount of Compoundof the Invention being metabolized and excreted from the body.Controlled- or sustained-release of an active ingredient can bestimulated by various conditions, including but not limited to, changesin pH, changes in temperature, concentration or availability of enzymes,concentration or availability of water, or other physiologicalconditions or compounds.

Controlled-release and sustained-release means for use according to thepresent invention may be selected from those known in the art. Examplesinclude, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and5,733,566, each of which is incorporated herein by reference. Suchdosage forms can be used to provide controlled- or sustained-release ofone or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, multiparticulates,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled- orsustained-release formulations known in the art, including thosedescribed herein, can be readily selected for use with the activeingredients of the invention in view of this disclosure. See alsoGoodson, “Dental Applications” (pp. 115-138) in Medical Applications ofControlled Release, Vol. 2, Applications and Evaluation, R. S. Langerand D. L. Wise eds., CRC Press (1984). Other controlled- orsustained-release systems that are discussed in the review by Langer,Science 249:1527-1533 (1990) can be selected for use according to thepresent invention. In one embodiment, a pump can be used (Langer,Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201(1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release(Langer and Wise eds., 1974); Controlled Drug Bioavailability, DrugProduct Design and Performance (Smolen and Ball eds., 1984); Ranger andPeppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)). In yet anotherembodiment, a controlled- or sustained-release system can be placed inproximity of a target of a Compound of the Invention, e.g., the spinalcolumn, brain, or gastrointestinal tract, thus requiring only a fractionof the systemic dose.

When in tablet or pill form, a pharmaceutical composition of theinvention can be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

Pharmaceutical compositions of the invention include single unit dosageforms suitable for oral administration such as, but not limited to,tablets, capsules, gelcaps, and caplets that are adapted for controlled-or sustained-release.

The amount of the Compound of the Invention that is effective for thetreatment or prevention of a condition can be determined by standardclinical techniques. In addition, in vitro and/or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on, e.g., the route ofadministration and the extent of the Condition to be treated, and can bedecided according to the judgment of a practitioner and/or eachpatient's circumstances. Variations in dosing may occur depending upontypical factors such as the weight, age, gender and physical condition(e.g., hepatic and renal function) of the patient being treated, theaffliction to be treated, the severity of the symptoms, the frequency ofthe dosage interval, the presence of any deleterious side-effects, andthe particular compound utilized, among other things.

Suitable effective dosage amounts can range from about 0.01 mg/kg ofbody weight to about 3000 mg/kg of body weight of the patient per day,although they are typically from about 0.01 mg/kg of body weight toabout 2500 mg/kg of body weight of the patient per day or from about0.01 mg/kg of body weight to about 1000 mg/kg of body weight of thepatient per day. In one embodiment, the effective dosage amount is about100 mg/kg of body weight of the patient per day or less. In anotherembodiment, the effective dosage amount ranges from about 0.01 mg/kg ofbody weight to about 100 mg/kg of body weight of the patient per day ofa Compound of the Invention, in another embodiment, about 0.02 mg/kg ofbody weight to about 50 mg/kg of body weight of the patient per day, andin another embodiment, about 0.025 mg/kg of body weight to about 20mg/kg of body weight of the patient per day.

Administration can be as a single dose or as a divided dose. In oneembodiment, an effective dosage amount is administered about every 24hours until the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 hours until the Conditionis abated. In another embodiment, an effective dosage amount isadministered about every 8 hours until the Condition is abated. Inanother embodiment, an effective dosage amount is administered aboutevery 6 hours until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 4 hours until theCondition is abated. The effective dosage amounts described herein referto total amounts administered; that is, if more than one Compound of theInvention is administered, the effective dosage amounts correspond tothe total amount administered.

Where a cell capable of expressing the μ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the μ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the δ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the δ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the κ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the κ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the ORL-1 receptor is contacted witha Compound of the Invention in vitro, the amount effective forinhibiting or activating the ORL-1 receptor function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the compound in a pharmaceutically acceptablecarrier or excipient. In one embodiment, the volume of solution orsuspension comprising the Compound of the Invention can be from about0.01 μL to about 1 mL. In another embodiment, the volume of solution orsuspension can be about 200 μL.

Compounds of the Invention can be assayed in vitro or in vivo for thedesired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.Certain Compounds of the Invention are expected to have an ED₅₀ fortreating inflammatory pain ranging from about 0.5 mg/kg to about 20mg/kg. Certain Compounds of the Invention are expected to producesignificant analgesia and/or anti-hyperalgesia at doses that do notinduce respiratory depression. In contrast, oxygen tension, oxygensaturation and pH are significantly decreased, while carbon dioxide issignificantly increased, in blood samples from rats given effectivedoses of conventional opioids, such as morphine.

According to the present invention, methods for treating or preventing aCondition in a patient in need thereof can further compriseco-administering to the patient an effective amount of a secondtherapeutic agent in addition to a Compound of the Invention (i.e., afirst therapeutic agent). An effective amount of the second therapeuticagent can be known or determinable by a medical practitioner in view ofthis disclosure and published clinical studies. In one embodiment of theinvention, where a second therapeutic agent is administered to a patientfor treatment of a Condition (e.g., pain), the minimal effective amountof the Compound of the Invention (i.e., the first therapeutic agent)will be less than its minimal effective amount would be in circumstanceswhere the second therapeutic agent is not administered. In thisembodiment, the Compound of the Invention and the second therapeuticagent can act either additively or synergistically to treat or prevent aCondition. Alternatively, the second therapeutic agent may be used totreat or prevent a disorder that is different from the Condition forwhich the first therapeutic agent is being administered, and whichdisorder may or may not be a Condition as defined hereinabove. In oneembodiment, a Compound of the Invention is administered concurrentlywith a second therapeutic agent as a single composition comprising aneffective amount of a Compound of the Invention and an effective amountof the second therapeutic agent. Alternatively, a composition comprisingan effective amount of a Compound of the Invention and a secondcomposition comprising an effective amount of the second therapeuticagent are concurrently administered. In another embodiment, an effectiveamount of a Compound of the Invention is administered prior orsubsequent to administration of an effective amount of the secondtherapeutic agent. In this embodiment, the Compound of the Invention isadministered while the second therapeutic agent exerts its therapeuticeffect, or the second therapeutic agent is administered while theCompound of the Invention exerts its therapeutic effect for treating orpreventing a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-IA inhibitor, a 5-lipoxygenaseinhibitor, an anti-emetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca²⁺-channel blocker, an anti-cancer agent, an agentfor treating or preventing UI, an agent for treating or preventinganxiety, an agent for treating or preventing a memory disorder, an agentfor treating or preventing obesity, an agent for treating or preventingconstipation, an agent for treating or preventing cough, an agent fortreating or preventing diarrhea, an agent for treating or preventinghigh blood pressure, an agent for treating or preventing epilepsy, anagent for treating or preventing anorexia/cachexia, an agent fortreating or preventing drug abuse, an agent for treating or preventingan ulcer, an agent for treating or preventing IBD, an agent for treatingor preventing IBS, an agent for treating or preventing addictivedisorder, an agent for treating or preventing Parkinson's disease andparkinsonism, an agent for treating or preventing a stroke, an agent fortreating or preventing a seizure, an agent for treating or preventing apruritic condition, an agent for treating or preventing psychosis, anagent for treating or preventing Huntington's chorea, an agent fortreating or preventing ALS, an agent for treating or preventing acognitive disorder, an agent for treating or preventing a migraine, anagent for treating, preventing or inhibiting vomiting, an agent fortreating or preventing dyskinesia, an agent for treating or preventingdepression, or any mixture thereof.

A composition of the invention is prepared by a method comprisingadmixing a Compound of the Invention with a pharmaceutically acceptablecarrier or excipient. Admixing can be accomplished using methods knownfor admixing a compound (or derivative) and a pharmaceuticallyacceptable carrier or excipient. In one embodiment, the Compound of theInvention is present in the composition in an effective amount.

The present invention also relates to a kit, comprising a sterilecontainer containing an effective amount of a Compound of the Inventionand instructions for therapeutic use.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES

The following abbreviations are used:

ACN acetonitrile

aq. aqueous

atm atmosphere(s)

° C. degrees Celcius

conc. concentrated

DAST (diethylamino)sulfur trifluoride

DCE 1,2-dichloroethane

DCM dichloromethane

DME 1,2-dimethoxyethane

DMF dimethylformamide

DMSO dimethylsulfoxide

Et₂O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

h hour(s)

HPLC high pressure liquid chromatography

MeOH methanol

min minute(s)

psi pounds per square inch

RT room temperature

satd. saturated

TFA trifluoroacetic acid

THF tetrahydrofuran.

Example 1

The following compounds were prepared according to literatureprocedures:

Compounds 1-3 can be prepared as described in, for example, Hupp C. D.,et al., Tetrahedron Lett., 2010, 51, 2359.

Compound 4 can be prepared as described in, for example, Nagase, H., etal., J. Org. Chem., 2011, 76, 2257.

Example 2(4bR,4′S,8aS,9S)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7,8,8a,9-tetrahydro-spiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′,10(5H)-trione(6)(4bR,4′S,8aS,9R,10R)-11-(cyclopropylmethyl)-8a,10-dihydroxy-3-methoxy-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′-dione(7)(4S,4′S,4a′S,7a′R,12b′S)-3′-(cyclopropylmethyl)-4a′-hydroxy-9′-methoxy-2′,3′,4′,4a′,5′,6′-hexahydro-1′H,7a′H-spiro[imidazolidine-4,7′-[4,12]methanobenzofuro[3,2-e]isoquinoline]-2,5,13′-trione(8)(4S,4′R,4a′S,7a′R,12b′S,13′R)-3′-(cyclopropylmethyl)-4a′,13′-dihydroxy-9′-methoxy-2′,3′,4′,4a′,5′,6′-hexahydro-1′H,7a′H-spiro[imidazazolidine-4,7′-[4,12]methanobenzofuro[3,2-e]isoquinoline]-2,5-dione(9)(4bS,4′S,8aR,9S,10R)-11-(cyclopropylmethyl)-10-hydroxy-3-methoxy-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′-dione(10)(4bR,4′S,8aS,9S)-8a-hydroxy-3-methoxy-11-methyl-7,8,8a,9-tetrahydrospiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′,10(5H)-trione(11)(4bR,4′S,8aS,9R,10R)-8a,10-dihydroxy-3-methoxy-11-methyl-5,7,8,8a,9,10-hexahydro-spiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′-dione(12)

(a) To a mixture of Compound 2 (2.820 g, 8.26 mmol, 1 eq) in EtOH (28mL) and water (28 mL) was added KCN (0.819 g, 12.58 mmol, 1.5 eq) and(NH₄)₂CO₃ (5.563 g, 57.9 mmol, 7 eq). The reaction mixture was heated at60° C. for 2 h. The reaction mixture was partitioned between DCM (150mL) and water (150 mL). The organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography (SiO₂, 0-70% acetone/hexanes) to give 2.25 g(74%) of Compound 5 as a cream-colored solid.

¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.87(d, J=2.6 Hz, 1H), 6.73 (dd, J=8.3, 2.6 Hz, 1H), 6.65 (s, 1H), 4.50 (s,1H), 3.69 (s, 3H), 2.99 (d, J=18.0 Hz, 1H), 2.89 (d, J=5.3 Hz, 1H),2.74-2.65 (m, 1H), 2.54-2.47 (m, 1H, overlap with DMSO peak), 2.41-2.34(m, 1H), 2.32-2.22 (m, 3H), 2.20-2.13 (m, 1H), 1.98-1.74 (m, 3H),1.38-1.30 (m, 1H), 1.27-1.20 (m, 1H), 0.99-0.92 (m, 1H), 0.89-0.77 (m,1H), 0.51-0.41 (m, 2H), 0.15-0.04 (m, 2H).

LC/MS, m/z=412 [M+H]⁺ (Calc: 411).

(b) Compound 5 (5.0 g, 12.15 mmol) was dissolved in 2M aq. H₂SO₄ (100mL), and a solution of CrO₃ (2.67 g, 26.7 mmol) in 2M aq. H₂SO₄ (15 mL)was added dropwise. The reaction mixture was allowed to stir at RTovernight. A second batch of CrO₃ (2.43 g, 24.3 mmol) in 2M aq. H₂SO₄(25 mL) was added and the mixture stirred 6 h. A third batch of CrO₃(2.43 g, 24.3 mmol) in 2M aq. H₂SO₄ (25 mL) was added and the mixturestirred overnight. The reaction was cooled to 0° C., Celite (3 g) wasadded and the reaction quenched by the addition of MeOH (5 mL) followedby careful addition of cone. NH₄OH (75 mL). The mixture was stirred for30 min and filtered. The filtrate was extracted with DCM, the extractsdried over Na₂SO₄ and concentrated to give 4.50 g (87%) of the titleCompound 6 as a tan solid.

¹H NMR (400 MHz, CD₃OD): δ 7.98 (d, J=8.8 Hz, 1H), 7.12 (s, 1H),7.03-6.95 (m, 1H), 3.89 (s, 3H), 3.24 (s, 1H), 2.78 (dd, J=11.8, 4.7 Hz,1H), 2.60-2.40 (m, 4H), 2.29 (td, J=13.0, 5.3 Hz, 1H), 2.14 (dd, J=12.8,7.0 Hz, 1H), 1.91 (td, J=12.5, 3.2 Hz, 1H), 1.74 (td, J=13.9, 4.0 Hz,1H), 1.53 (d, J=13.4 Hz, 1H), 1.41 (d, J=13.2 Hz, 1H), 1.27 (d, J=11.9Hz, 1H), 1.02-0.90 (m, 1H), 0.51 (ddd, J=13.2, 8.6, 4.6 Hz, 2H),0.37-0.25 (m, 1H), 0.08 (dd, J=8.8, 4.0 Hz, 1H).

LC/MS, m/z=426 [M+H]⁺ (Calc: 425).

(c) To a solution of Compound 6 (645 mg, 1.516 mmol) in EtOH (20 mL) wasadded NaBH₄ (688 mg, 18.19 mmol) and the mixture stirred at RTovernight. The mixture was concentrated and purified by flashchromatography (SiO₂, 0-50% (10% NH₄OH in MeOH) in DCM) to give 120 mg(19%) of the title Compound 7 as a white solid.

¹H NMR (400 MHz, CD₃OD): δ 7.63-7.29 (m, 1H), 7.02-6.59 (m, 2H), 4.95(d, J=5.7 Hz, 1H), 3.78 (s, 3H), 3.09-2.98 (m, 2H), 2.81-2.69 (m, 2H),2.51-2.38 (m, 3H), 2.35-2.27 (m, 1H), 2.19-2.04 (m, 1H), 1.73 (td,J=13.9, 4.0 Hz, 1H), 1.41 (d, J=13.6 Hz, 1H), 1.32-1.19 (m, 1H), 1.03(d, J=11.7 Hz, 1H), 0.98-0.88 (m, 1H), 0.55-0.45 (m, 2H), 0.15 (dt,J=8.0, 4.3 Hz, 2H).

LC/MS, m/z=428 [M+H]⁺ (Calc: 427).

In a similar manner the following compounds were prepared:

(d) Compound 8 TFA salt:

¹H NMR (400 MHz, CD₃OD): δ 7.62 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.6 Hz,1H), 5.00-4.92 (m, 1H), 4.17-4.12 (m, 1H), 4.07-3.97 (m, 3H), 3.22 (dd,J=13.3, 6.5 Hz, 1H), 2.89-2.70 (m, 3H), 2.50-2.36 (m, 1H), 1.91-1.62 (m,4H), 1.48-1.34 (m, 1H), 0.90-0.80 (m, 1H), 0.79-0.64 (m, 2H), 0.53 (dq,J=9.6, 4.8 Hz, 2H).

LC/MS, m/z=440 [M+H]⁺ (Calc: 439).

(e) Compound 9 TFA salt:

¹H NMR (400 MHz, DMSO-d₆): δ 10.93 (s, 1H), 8.58-8.28 (m, 1H), 7.49 (s,1H), 7.42-7.26 (m, 1H), 7.15-7.00 (m, 2H), 6.74 (d, J=6.6 Hz, 1H), 6.59(s, 1H), 5.24 (t, J=5.5 Hz, 1H), 4.77-4.65 (m, 1H), 4.13-3.95 (m, 2H),3.93-3.78 (m, 3H), 3.15-2.97 (m, 1H), 2.88-2.70 (m, 2H), 2.30-2.15 (m,1H), 1.92-1.72 (m, 1H), 1.67-1.35 (m, 3H), 0.89-0.72 (m, 1H), 0.65 (d,J=6.2 Hz, 2H), 0.51 (d, J=4.2 Hz, 1H).

LC/MS, m/z=442 [M+H]⁺ (Calc: 441).

(f) Compound 10 TFA salt:

¹H NMR (400 MHz, DMSO-d₆): δ 10.73-10.60 (m, 1H), 8.85-8.69 (m, 1H),7.41 (s, 1H), 6.97 (s, 2H), 6.93-6.80 (m, 2H), 4.92-4.85 (m, 1H),3.89-3.79 (m, 1H), 3.57 (br. s., 3H), 3.05-2.82 (m, 2H), 2.56 (d, J=14.1Hz, 2H), 2.41-2.30 (m, 1H), 2.05-1.87 (m, 1H), 1.88-1.69 (m, 2H),1.56-1.39 (m, 3H), 1.28-1.15 (m, 1H), 1.16-0.97 (m, 1H), 0.71-0.47 (m,2H), 0.48-0.24 (m, 2H).

LC/MS, m/z=412 [M+H]⁺ (Calc: 411).

(g) Compound 11:

¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.13(s, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.97 (dd, J=2.3 Hz, 8.7 Hz, 1H), 4.75(s, 1H), 3.82 (s, 3H), 2.77 (s, 1H), 2.50-2.40 (m, 1H), 2.38 (d, 14.5Hz, 1H), 2.32-2.20 (m, 1H), 2.20-2.10 (m, 5H), 1.80-1.60 (m, 2H),1.35-1.25 (m, 1H), 1.20-1.10 (m, 1H), 1.10-1.00 (m, 1H).

LC/MS, m/z=386 [M+H]⁺ (Calc: 385).

(h) Compound 12:

¹H NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 1H), 7.42 (d, J=9.1 Hz, 1H),6.85-6.78 (m, 2H), 6.75 (s, 1H), 5.41-5.28 (m, 1H), 4.85-4.72 (m, 1H),4.58 (s, 1H), 3.70 (s, 3H), 2.73 (d, J=5.2 Hz, 1H), 2.68 (s, 3H),2.35-2.15 (m, 4H), 2.15-2.05 (m, 1H), 2.00-1.85 (m, 1H), 1.80-1.65 (m,1H), 1.35 (m, 1H), 1.18 (d, J=12.9 Hz, 1H), 0.83 (d, J=12.4 Hz, 1H).

LC/MS, m/z=388 [M+H]⁺ (Calc: 387).

Example 3(4bR,4′S,8aS,9S)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7,8,8a,9-tetrahydrospiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′,10(5H)-trione(13)(4bR,4′S,8aS,9R,10R)-11-(cyclopropylmethyl)-3,8a,10-trihydroxy-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′-dione(14)(4S,4′S,4a′S,7a′R,12b′S)-3′-(cyclopropylmethyl)-4a′,9′-dihydroxy-2′,3′,4′,4a′,5′,6′-hexahydro-1′H,7a′H-spiro[imidazolidine-4,7′-[4,12]methanobenzofuro[3,2-e]isoquinoline]-2,5,13′-trione (15)(4S,4′R,4a′S,7a′R,12b′S,13′R)-3′-(cyclopropylmethyl)-4a′,9′,13′-trihydroxy-2′,3′,4′,4a′,5′,6′-hexahydro-1′H,7a′H-spiro[imidazolidine-4,7′-[4,12]methanobenzofuro[3,2-e]isoquinoline]-2,5-dione (16)(4bR,4′S,8aS,9R,10R)-3,8a,10-trihydroxy-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′-dione(17)

To a solution of Compound 6 (320 mg, 0.752 mmol) in DCM (20 mL), cooledto 0° C., was added a 1.0M solution of BBr₃ in DCM (0.752 mL, 0.752mmol) dropwise via syringe. The reaction mixture was warmed to RT andstirred for 2 h. The reaction was quenched by the addition of satd. aq.NaHCO₃ (5 mL) and the volatiles were removed under reduced pressure. Theresidue was purified by flash chromatography (SiO₂, 0-20% (10% NH₄OH inMeOH) in DCM) to give to give 30 mg (10%) of Compound 13 TFA salt as awhite solid.

¹H NMR (400 MHz, CD₃OD): δ 7.95 (d, J=8.8 Hz, 1H), 6.95 (d, J=2.0 Hz,1H), 6.87-6.80 (m, 1H), 3.92 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br.s., 1H), 2.62 (br. s., 1H), 2.54-2.46 (m, 2H), 2.45-2.40 (m, 1H),2.39-2.30 (m, 2H), 1.83 (td, J=14.1, 3.9 Hz, 1H), 1.60 (d, J=13.6 Hz,1H), 1.40 (d, J=11.7 Hz, 2H), 1.24 (br. s., 1H), 0.71 (d, J=4.6 Hz, 1H),0.67-0.52 (m, 2H), 0.37 (d, J=4.2 Hz, 1H).

LC/MS, m/z=412 [M+H]⁺ (Calc: 411).

In a similar manner the following compounds were prepared:

(a) Compound 14 TFA salt:

¹H NMR (400 MHz, DMSO-d₆): δ 10.75-10.60 (m, 1H), 9.47-9.27 (m, 1H),8.42-8.07 (m, 1H), 7.39-7.24 (m, 1H), 6.98 (s, 1H), 6.71 (s, 2H),6.64-6.51 (m, 1H), 6.07 (s, 1H), 5.76-5.58 (m, 1H), 5.08-4.77 (m, 1H),4.22-4.06 (m, 1H), 3.98-3.68 (m, 2H), 2.32-2.02 (m, 4H), 1.89-1.71 (m,1H), 1.70-1.50 (m, 1H), 1.37-1.15 (m, 2H), 1.14-0.90 (m, 1H), 0.68-0.58(m, 1H), 0.58-0.47 (m, 2H), 0.58-0.47 (m, 2H), 0.44-0.33 (m, 1H).

LC/MS, m/z=414 [M+H]⁺ (Calc: 413).

(b) Compound 15 TFA salt:

¹H NMR (400 MHz, CD₃OD): δ 7.63-7.29 (m, 1H), 7.01-6.67 (m, 1H), 4.86(s, 1H), 4.01 (br. s., 1H), 3.95-3.86 (m, 1H), 3.14-3.05 (m, 1H),2.78-2.57 (m, 3H), 2.31 (td, J=13.4, 3.5 Hz, 1H), 1.79-1.53 (m, 4H),1.36-1.21 (m, 1H), 0.79-0.70 (m, 1H), 0.69-0.61 (m, 1H), 0.61-0.53 (m,1H), 0.47-0.37 (m, 1H).

LC/MS, m/z=426 [M+H]⁺ (Calc: 425).

(c) Compound 16:

¹H NMR (400 MHz, CD₃OD): δ 6.89-6.83 (m, 1H), 6.75-6.65 (m, 1H),6.75-6.65 (m, 1H), 5.11-5.03 (m, 1H), 4.70-4.59 (m, 1H), 2.88 (dd,J=12.7, 4.7 Hz, 2H), 2.79-2.64 (m, 1H), 2.47-2.34 (m, 1H), 2.33-2.20 (m,1H), 1.69-1.45 (m, 3H), 1.41-1.30 (m, 1H), 1.22 (d, J=18.0 Hz, 2H),0.58-0.48 (m, 2H), 0.34-0.20 (m, 2H).

LC/MS, m/z=428 [M+H]⁺ (Calc: 427).

(d) Compound 17:

¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 1H), 9.12 (s, 1H), 7.31 (d, J=9.0Hz, 1H), 6.73 (s, 1H), 6.69-6.60 (m, 2H), 5.50-5.05 (brs, 1H), 4.78 (d,J=4.3 Hz, 1H), 4.70-4.40 (brs, 1H), 2.80-2.60 (m, 4H), 2.40-2.18 (m,3H), 2.14 (d, J=14.2 Hz, 1H), 2.05-1.85 (m, 2H), 1.85-1.65 (m, 1H), 1.35(d, J=12.7 Hz, 1H), 1.18 (d, J=12.6 Hz, 1H), 0.81 (d, J=11.8 Hz, 1H).

LC/MS, m/z=374 [M+H]⁺ (Calc: 373).

Example 4(4bR,4′S,8aS,9S,10R)-11-(cyclopropylmethyl)-10-fluoro-8a-hydroxy-3-methoxy-5,7,8,8a,9,10-tetrahydrospiro[9,4b-(epiminoethano)phenanthrene-6,4′-imidazolidine]-2′,5′-dione (18)

A solution of Compound 7 (420 mg, 0.98 mmol) in DCM (20 mL) cooled to−40° C. was added DAST (317 mg, 1.97 mmol). The mixture was stirred at−40° C. for 10 min and at RT for 1 h. The mixture was concentrated andpurified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in ACN/0.1%TFA in water) to give 7 mg (2%) of Compound 18 TFA salt as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), 8.96-8.85 (m, 1H), 7.40 (s,1H), 7.04 (br. s., 4H), 6.52-6.31 (m, 1H), 6.30-5.98 (m, 1H), 4.33-4.20(m, 1H), 3.77 (s, 5H), 3.03-2.87 (m, 2H), 1.86-1.62 (m, 3H), 1.33-1.15(m, 4H), 0.73 (br. s., 1H), 0.59 (br. s., 2H), 0.44 (br. s., 1H).

LC/MS, m/z=416 [M+H]⁺ (Calc: 415).

Example 5

The following Tables provide results on the efficacy of binding andactivity response of exemplified Compounds of the Invention at the μ-and κ-opioid receptors.

In TABLE 1, binding affinity of certain Compounds of the Invention tothe μ- and κ-opioid receptors was determined as described above forbinding assays using HEK-293 cells.

In TABLE 2, activity response of certain Compounds of the Invention tothe μ- and κ-opioid receptors was determined as described above forfunctional assays using U-2 OS cells.

TABLE 1 Binding Affinity of Certain Compounds of the Invention OpioidReceptor K_(i) (nM) Compound No. Structure μ κ 6

>20 μM 1055 ± 84.6 7

>20 μM >20 μM 8

>20 μM >20 μM 9

>20 μM >20 μM 10

>20 μM 3583 ± 647.2 11

>20 μM >20 μM 12

12622 >20 μM 13

471.6 ± 40.8 12.2 ± 0.61 14

1016 ± 52.1 78.1 ± 21.0 15

15408 ± 3126 2524 ± 707.7 16

>20 μM >20 μM

TABLE 2 Activity Response of Certain Compounds of the Invention Com-Opioid Receptor pound μ κ No. EC₅₀ (nM) E_(max) (%) EC₅₀ (nM) E_(max)(%) 13 37.5 ± 6.18 61.3 ± 5.78 8.79 ± 1.26 106.0 ± 2.52 14 ND ND 182.7 ±17.3  111.3 ± 2.91 17 116.0 ± 23.0  98.8 ± 0.97 5780 ± 1105 107.0 ± 1.5318  1553 ± 184.3 14.7 ± 0.33  1476 ± 125.0  81.7 ± 0.88 ND = notdetermined

The in vitro test results of Tables 1 and 2 show that representativeCompounds of the Invention activate these receptors as partial to fullagonists. Compounds of the Invention are therefore expected to be usefulto treat Conditions, particularly pain, that are responsive to theactivation of one or more opioid receptors.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents, patent applications, and publications cited herein arefully incorporated by reference herein in their entirety.

1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ ishydrogen, hydroxy, halo, cyano, carboxy, or aminocarbonyl; or alkyl,alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein saidaryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl areoptionally substituted with 1, 2, or 3 independently selected R¹⁰groups; or —O-PG, wherein PG is a hydroxyl protecting group; R² is (a)hydrogen or carboxamido; or (b) alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl,alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups; R³ ishydrogen, hydroxy, or halo; or alkoxy, alkylamino, or dialkylamino, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl,and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹⁰ groups; R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen; cycloalkyl;cycloalkenyl; heterocyclo; aryl; heteroaryl; alkyl optionallysubstituted with 1 or 2 substituents, each independently selected fromthe group consisting of hydroxy, halo, haloalkyl, cyano, nitro, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, carboxamido,cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl; and anamine protecting group; wherein said cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl are optionally substituted with 1, 2,or 3 independently selected R¹⁰ groups; R⁶ is hydrogen and R⁷ ishydroxy, halogen, alkyl, or alkoxy; or R⁶ and R⁷ together form ═O; R⁸and R⁹ are both hydrogen; or R⁸ and R⁹ together with the carbon atoms towhich they are attached form a linker —O—; each R¹⁰ is independentlyselected from the group consisting of hydroxy, halo, alkyl, haloalkyl,cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, andalkoxycarbonyl; Y is C═O or CH₂; and Z is C═O or CHR¹¹; wherein R¹¹ ishydrogen, C₁₋₆ alkyl or phenyl optionally substituted with 1, 2, or 3independently selected R¹⁰ groups.
 2. (canceled)
 3. The compound ofclaim 1, having the Formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁷and Y are as defined in claim
 1. 4. (canceled)
 5. The compound of claim1, having the Formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁷and Y are as defined in claim
 1. 6. (canceled)
 7. The compound of claim1, having the Formula VII:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁵,R⁷, and Y are as defined in claim
 1. 8. The compound of claim 1, havingthe Formula VIII:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁵and Y are as defined in claim
 1. 9-11. (canceled)
 12. The compound ofclaim 1, having the Formula XII:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁷,Y, and Z are as defined in claim
 1. 13. (canceled)
 14. The compound ofclaim 1, having the Formula XIV:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁵and Y are as defined in claim
 1. 15. The compound of claim 1, having theFormula XV:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁵,R⁷ and Y are as defined in claim
 1. 16. (canceled)
 17. The compound ofany one of claims 1-16, or a pharmaceutically acceptable salt or solvatethereof, wherein R¹ is hydroxy, or unsubstituted C₁₋₆ alkoxy. 18-22.(canceled)
 23. The compound of claim 1, or a pharmaceutically acceptablesalt or solvate thereof, wherein R² is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,(cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R¹⁰ groups. 24-25.(canceled)
 26. The compound of claim 23, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² iscyclopropyl(C₁₋₄)alkyl, optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl. 27.(canceled)
 28. The compound of claim 5, having the Formula XVI:

or a pharmaceutically acceptable salt and solvate thereof, wherein R¹²is H or C₁₋₆ alkyl optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of hydroxy, halo,halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy,C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl, and R³, R⁶, R⁷, and Y are asdefined in claim
 5. 29. The compound of claim 28, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R³ is hydrogen or hydroxy.30-36. (canceled)
 37. The compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is C═O and R⁴ and R⁵ areboth hydrogen.
 38. The compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is CH₂ and R⁴ and R⁵ areboth hydrogen. 39-43. (canceled)
 44. The compound of claim 1, selectedfrom the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 45. Apharmaceutical composition, comprising a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltor solvate thereof, and one or more pharmaceutically acceptablecarriers. 46-49. (canceled)
 50. A method of treating pain in a patient,comprising administering an effective amount of a compound of claim 1,or a pharmaceutically acceptable salt or solvate thereof, to the patientin need of such treatment or prevention.
 51. (canceled)
 52. The methodof claim 50, wherein said pain is acute pain, chronic pain or surgicalpain, wherein said chronic pain is neuropathic pain, postoperative pain,or inflammatory pain. 53-54. (canceled)
 55. A method of modulating oneor more opioid receptors in a patient, comprising administering to thepatient an effective amount of a compound as claimed in claim 1, or apharmaceutically acceptable salt or solvate thereof, wherein the μ- orκ-opioid receptor is modulated, or both the μ- and κ-opioid receptorsare modulated. 56-86. (canceled)
 87. A compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, wherein thecompound is ³H, ¹¹C, or ¹⁴C radiolabeled. 88-90. (canceled)